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Notes: Abstract Purpose: The premise for the study was that topotecan (TPT) resistance in preclinical studies is associated with low level expression of the p-glycoprotein (Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR) phenotype, which might be overcome in clinical practice by administering moderately (2.3-fold) higher doses of TPT that have been shown to be feasible with granulocyte colony-stimulating factor (G-CSF) support. This phase II study evaluated the anti-tumor activity of TPT administered at its highest possible solid tumor dose with G-CSF in patients with fluoropyrimdine-refractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. Patients and methods: TPT was administered as a 30-minute infusion daily for five days every three weeks at a dose of 3.5 mg/m2/day to patients with advanced colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-based chemotherapy for advanced disease or within six months after receiving fluoropyrimdine-based adjuvant chemotherapy. This dose of TPT was previously determined to be the maximal tolerated dose (MTD) with G-CSF support in a phase I study involving solid tumor patients with similar risk factors for myelosuppression. Plasma sampling was performed during course 1 to characterize the pharmacokinetic (PK) and PD behavior of TPT. Results: Seventeen patients who received 89 courses of TPT and G-CSF were evaluable for toxicity; 16 patients were evaluable for anti-tumor response. Toxicity, particularly myelosuppression, was substantial. At the 3.5 mg/m2/day dose level, absolute neutrophil counts (ANC) were less than 500/µl for longer than five days in 17% of courses involving seven of 17 (41%) patients. Severe neutropenia associated with fever occurred in 12.3% of courses; and platelet counts below 25,000/µl were noted in 26.9% of courses. These toxicities resulted in dose reductions in seven of 17 (41%) patients. Nevertheless, 90% of the planned total dose of TPT was administered. No major responses were observed, though minor activity was noted in several patients. Both the median time to progression and the median survival time were short – 2.5 and four months, respectively. Although interindividual variability in the disposition of total TPT was observed, the lack of objective responses precluded PD assessments related to disease activity. Total TPT exposure was significantly higher than drug exposure achieved in similar patients at an identical dose in a previous phase I study of TPT and G-CSF, which may explain why more severe myelosuppressive effects occurred in the present study. There were no PD relationships evident between relevant PK parameters and the percent decrements in platelets and ANCs during course 1, although patients with severe toxic effects (ANC below 500/µl for more than five days and/or platelets 〈25,000/µl) had higher drug exposure than patients with less severe toxicity (P 〈 0.018 and P = 0.09, respectively). Conclusions: Based on these results, the true response rate of TPT at its solid tumor MTD with G-CSF support is unlikely to approach 20%. Although a response rate of less than 20% might be viewed as significant in this disease setting and might be confirmed with sufficient statistical certainty by treating additional patients, the substantial toxicity, inconvenience, and cost associated with this high dose TPT/G-CSF regimen does not warrant the acceptance of a lower level of anti-tumor activity as a criterion for further development.

Notes: Abstract Background: Irinotecan (CPT-11) is metabolized by esterase to form a SN-38, which is further conjugated by UGT1A1. Genetic polymorphism has been shown in a promoter region of UGT1A1 and is related to its activity. We investigated whether there might be an inter-individual difference in pharmacokinetics of SN-38 and its glucuronide, depending on the genotypes of UGT1A1. Patients and methods: Nine male patients with lung cancer were treated with irinotecan (50 mg/m2) and carboplatin. Pharmacokinetic parameters were calculated with full sampling plasma data. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Results: The genotyping analysis revealed one heterozygote (6/7) and one homozygote (7/7) for (TA)7TAA allele (UGT1A1*28). The remaining seven patients were homozygote for (TA)6TAA allele (6/6, wild type). The metabolic ratios (SN-38/SN-38 glucuronide) in the patient with 7/7 genotype were uncharacteristically higher than those in the patients with other genotypes (6/6 and 6/7). Biliary index was 6980 versus 2180 ± 1110 (range 840–3730) in patients with 7/7 versus 6/6 genotypes, respectively. Conclusion: These results support the idea that the patient with 7/7 genotype has an impaired capacity for glucuronidation of SN-38.

Notes: Abstract Purpose: DMP 840, a novel bisnaphthalimide, has demonstrated promising schedule dependent anti-tumor activity in vitro and in vivo against several tumor cell lines. A phase I study was conducted to evaluate the effect of a 24-hour infusion schedule repeated every three weeks, on the therapeutic efficacy of DMP 840. Patients and methods: Fourteen patients with refractory solid tumor malignancies were treated with DMP 840 at doses of 20, 40, 50 and 60 mg/m2. Results: A combination of neutropenia, thrombocytopenia and stomatitis were dose-limiting at doses of 50 and 60 mg/m2 in both minimally- and extensively-pretreated patients. In contrast, all courses at lower dose levels were well tolerated. Pharmacokinetic analysis demonstrated that DMP 840 had a prolonged terminal half life (median 39 hours; range 25–86) and that dose-limiting events were significantly related to several indices of systemic DMP 840 exposure (P 〈 0.01, Wilcoxon Rank Sum test). Conclusion: The recommended dose of DMP 840 for further disease oriented evaluations is 40 mg/m2 administered over 24 hours every three weeks. The infusion duration evaluated in this study did not result in a substantial increase in the tolerable dose compared to shorter, less cumbersome schedules.

Notes: Abstract Background: In clinical trials in the USA, IDEC-C2B8 (a mouse-humanchimeric anti-CD20 monoclonal antibody) has demonstrated high response rateswith only mild toxic effects in relapsed B-cell lymphoma at a dose of fourweekly 375 mg/m2 infusions. The aim of the present trial wasto determine whether or not this dose is practically applicable to Japanesepatients with relapsed B-cell lymphoma with respect to safety,pharmacokinetics and efficacy. Patients and methods: Patients with relapsed CD20+ B-cell lymphomareceived intravenous infusions of IDEC-C2B8 once a week for four weeks. Atotal of 12 patients (four at 250 mg/m2 and eight at 375mg/m2) were enrolled. Results: All 11 eligible patients treated with either dose leveltolerated IDEC-C2B8 well. Commonly observed adverse drug reactions weregrades 1 or 2 non-hematologic toxicities during the infusion, consistingmostly of flu-like symptoms and skin reactions. All of the observedhematologic toxicities were of grade 3 or less, and transient. A rapid andsustained B-cell decrease in peripheral blood was observed, but noinfectious episodes were encountered. Human anti-mouse and anti-chimericantibodies were not detected. Of the 11 eligible patients (eight withfollicular, two with diffuse large-cell and one with mantle cell lymphoma),two showed a complete response and five showed a partial response, and allof the seven responders had lymphoma with follicular histology. Apharmacokinetic analysis showed that the elimination half-life (T1/2) ofIDEC-C2B8 was 445 ± 361 hours, and that the serum antibody levelsincreased in parallel with the course of infusions, and in most patients wasstill measurable at three months. Conclusions: The dose of four weekly 375 mg/m2 infusionsof IDEC-C2B8 is safe and effective in Japanese patients with relapsed B-celllymphoma. Further studies evaluating IDEC-C2B8 are warranted.

Notes: Summary [Ne-palmitoyl Lys (B29)] human insulin is a fatty acid-acylated derivative of insulin with extended action compared to unmodified insulin when infused intravenously (i. v.) secondary to its binding to circulating albumin. The duration and activity profile of the acylated (A) and NPH (B) insulins were assessed following subcutaneous (s. c.) doses of (A) 6 nmol/kg and (B) 1.2 nmol/kg (equivalent to 0.2 U/kg) in 9 subjects with IDDM. After overnight i.v infusion of regular human insulin, morning glucose was (A) 6.9 ± 0.1 and (B) 6.8 ± 0.1 mmol/l. After the s. c. injection, i. v. human insulin or glucose was infused to maintain near-basal glycaemia and tracer glucose to assess hepatic glucose production (HGP). An activity profile was deduced for each study by expressing the glucose infusion rate at each time point, as a fraction (%) of the basal (measured) HGP, and the i. v. insulin infusion rate as a fraction (%) of the basal requirement. The two fractions are combined by adding the fractional glucose infusion rate and subtracting the fractional insulin infusion rate. Infusion rates of i. v. insulin in the morning were (A) 0.96 ± 0.096 and (B) 1.22 ± 0.09 pmol · kg–1· min–1. After insulin injection, i.v insulin requirements decreased and were below 10 % of basal between 100 and 150 min. A constant activity profile of 0 % represents a perfect substitution of the basal i. v. insulin infusion by the s. c. dose. The actual profile is defined by deviations from this (above) and was –17 ± 11, 7 ± 10, –9 ± 6 and –18 ± 18 % for [Ne-palmitoyl Lys (B29)] human insulin and 17 ± 12, 5 ± 6, –9 ± 15, 22 ± 18 % for NPH insulin at 3, 6, 9 and 12 h after s. c. injection. HGP was similar for the two insulins, demonstrating similar metabolic actions and profiles both peripherally and at the liver. [Diabetologia (1998) 41: 116–120]

Notes: Abstract This retrospective study served to examine the correlation between the degree of cyclosporin (CyA) exposure, as estimated by a single pharmacokinetic (PK) profile performed at 1 week post-transplant, and the outcome of 290 consecutive renal transplants performed over a 6-year period. For this retrospective analysis patients were stratified into four historical groups based on 12- versus 24-h PK studies and on the use of radioimmunoassay versus fluorescence polarization immunoassay methods for estimates of CyA concentrations. Four PK measures – trough concentration (C0), average concentration values (Cav; i. e., the dosing interval-corrected area under the concentration-time curve), maximum concentration (Cmax), and time to maximum concentration (tmax) – were examined as predictors of patient, graft, and rejection-free survival rates for each of the four groups individually and for all groups combined. Patients with an initial Cav≥ 550 ng/ml had higher 1-year (88 %) and 6-year (66 %) graft survival rates than patients with Cav 〈 550 ng/ml, who had 1- and 6-year graft survival rates of 80 % and 59 %, respectively (P = NS). Statistically significant differences were observed in graft survival rates between patients with Cav 〈 550 versus Cav≥ 550 ng/ml at 30 (88 % vs 96 %; P 〈 0.02), 60 (85 % vs 94 %; P 〈 0.007), 90 (85 % vs 94 %; P 〈 0.02), and 180 (83 % vs 92 %; P 〈 0.05) days. Moreover, patients with Cav 〈 550 ng/ml displayed more severe rejection episodes, as judged by Banff classification, than patients who displayed Cav≥ 550 ng/ml (grades II and III; 71 % vs 50 %; P = 0.036). In contrast, the C0, Cmax, and tmax values did not correlate with patient, graft, or rejection-free survival rates. The pharmacokinetic parameter of Cav correlated strongly with early graft survival and may, therefore, be a useful predictor of those renal transplant patients who may require more intensive post-transplant monitoring of CyA concentrations by serial PK studies to improve graft survival.

Notes: Abstract Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.

Notes: Abstract Background: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethyl-amino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days. Patients and methods: 45 patients (7 female, 38 male; median age 54 [range 37–73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria. Results: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2γ) was 14.7 ± 3.7 h. The AUC at 250 mg/m2 was determined to be 330 ± 147 μg/mlh, the plasma clearance of NK611 was 16.2 ± 8.2 ml/min · m2 and the Vss was 16.8 ± 3.3 l/m2. Protein binding of NK611 was 98.7%. Conclusion: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.

Notes: Abstract Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiogenic agent in clinical development for cancer treatment. It has been postulated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady state maximum concentrations when taken without regard to meals vs. fasting. The purpose of this study was to determine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ function were randomized to receive two doses of CAI (250 mg/m 2 ) with and without a standardized high fat meal. One cohort of 6 patients received these doses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacokinetic (PK) models were fit to the concentration–time data. PK parameters were ultimately calculated using a model which allows simultaneous estimation of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC 0–t was determined using the trapezoidal method, extrapolated to infinity, and used to calculate the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However, the relative bioavailability, as measured by AUC 0–∞, of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 μg * hr/ml; p=0.0005). The magnitude of the increase in relative bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eating.

Notes: Abstract A two-way crossover study was conducted in crossbred male calves (6–8 months old) to determine the bioavailability, pharmacokinetics and dosage regimens for a long-acting formulation of oxytetracycline (OTC-LA). The half-lives of oxytetracycline after intravenous and intramuscular administration were 7.8 h and 24 h, respectively. The volume of distribution and total body clearance values of the drug were 0.86±0.07 L and 76.1±3.3 (ml/h)/kg, respectively. The maximum concentration of the drug in the serum (4.7–7.4 μg/ml) was achieved 8–10 h after intramuscular administration. The minimum therapeutic serum concentration of drug of ≥0.5 μg/ml was maintained between 15 min and 84 h after intramuscular administration. The intramuscular bioavailability of the drug was 89.1±4.2%. The dosage regimens to maintain the minimum therapeutic serum concentrations of OTC following intramuscular administration of OTC-LA were computed.

Notes: Abstract Two trials were conducted against natural and experimentally induced parasitic gastroenteritis in sheep and goats using an in-feed formulation of albendazole to evaluate its therapeutic and prophylactic efficacy. In the first trial, albendazole was incorporated in feed pellets to deliver an average daily dose of 0.7 mg/kg body weight in order to evaluate its prophylactic efficacy. In the second trial, feed pellets were offered to deliver an average total dose of 8.0 mg/kg body weight in two equal split doses in order to evaluate its curative efficacy. Sustained plasma concentrations of the active compound, albendazole sulphoxide, and its metabolite albendazole sulphone, sufficient to prevent establishment of infection, were achieved when the animals were allowed to feed on medicated pellets for 10 consecutive days. The bioavailability of the metabolites of albendazole following the administration of a therapeutic dose in two split doses of the in-feed formulation was sufficient to remove established adult nematodes. The concentrate feed pellets could be used for self-medicating small ruminants for therapeutic use as well as for prophylaxis based on their strategic use appropriate to the epidemiology of the parasitic disease.

Notes: Abstract The synthetic androgen 19-nortestosterone (β-NT) has been used illegally as a growth promoter in cattle production in the European Union. Elimination of β-NT and its metabolites in plasma, urine and bile was studied in three cattle with cannulated gallbladders following intramuscular injection at a single site of 500 mg of the laurate ester (NTL) containing 300.5 mg β-NT. Using enzyme immunoassay quantification, plasma Cmax of free β-NT was 0.5±0.15 μg/L (mean±SEM). Concentrations of free β-NT in plasma were consistently greater than the assay limit of quantification (0.12 μg/L) for 32.7±13.42 days. Mean residence time for free β-NT in plasma was 68.5±20.75 days. Following sample preparation by immunoaffinity chromatography, high-resolution GC-MS was used to quantify β-NT and α-NT in urine and bile. β-NT was detected irregularly in urine from two of the three animals post injection. The principal metabolite present in the urine, α-NT, was detected for 160.3±22.67 days post injection. Cmax for α-NT in urine was 13.7±5.14 μg/L. Mean urinary AUC0–183 days for α-NT was 845.7±400.90 (μg h)/L. In bile, α-NT was the only metabolite detected for 174.3±8.67 days post treatment. Cmax for α-NT in bile was 40.8±12.70 μg/L and mean biliary AUC0–183 days for α-NT was 1982.6±373.81 (μg h)/L. Concentrations of α-NT in bile samples were greater than those in urine samples taken at the same time. The mean ratio of biliary:urinary AUC0–183 days was 3.0±0.72. It is concluded that bile is a superior fluid for detection of α-NT following injection of NTL, owing to the longer period during which residues may be detected after administration.

Notes: Abstract The pharmacokinetics of albendazole was studied in sheep following single oral and intraruminal administration at nematocidal dose rates. The disposition curves of its metabolites indicated increased uptake of the drug in sheep following intraruminal as compared to oral dosing (p〈0.05). The increased bioavailability of benzimidazole anthelmintics given by the intraruminal route could be exploited for optimizing the use of anthelmintic for sustained parasite control in small ruminants.

Notes: Abstract Lumping is a common pragmatic approach aimed at the reduction of whole-body physiologically based pharmacokinetic (PBPK) model dimensionality and complexity. Incorrect lumping is equivalent to model misspecification with all the negative consequences to the subsequent model implementation. Proper lumping should guarantee that no useful information about the kinetics of the underlying processes is lost. To enforce this guarantee, formal standard lumping procedures and techniques need to be defined and implemented. This study examines the lumping process from a system theory point of view, which provides a formal basis for the derivation of principles and standard procedures of lumping. The lumping principle in PBPK modeling is defined as follows: Only tissues with identical model specification, and occupying identical positions in the system structure should be lumped together at each lumping iteration. In order to lump together parallel tissues, they should have similar or close time constants. In order to lump together serial tissues, they should equilibrate very rapidly with one another. The lumping procedure should include the following stages: (i) tissue specification conversion (when tissues with different model specifications are to be lumped together); (ii) classification of the tissues into classes with significantly different kinetics, according to the basic principle of lumping above; (iii) calculation of the parameters of the lumped compartments; (iv) simulation of the lumped system; (v) lumping of the experimental data; and (vi) verification of the lumped model. The use of the lumping principles and procedures to be adopted is illustrated with an example of a commonly implemented whole-body physiologically based pharmacokinetic model structure to characterize the pharmacokinetics of a homologous series of barbiturates in the rat.

Notes: Abstract A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.

Notes: Abstract We describe a method of rapidly obtaining a specified steady state plasma concentration of an intravenous drug within precise limits. The technique requires an initial bolus to raise the plasma concentration to the upper limit followed by a series of constant-rate infusions each of which is associated with a minimum plasma concentration equal to the tower limit. The infusion rate is stepped down when the plasma concentration returns to the upper limit. Computer simulation, based on the method, is used to generate plasma concentration–time curves with fluctuations of up to 10% about selected steady state concentrations of amrinone, esmolol, lidocaine, midazolam, propofol, and theophylline. The utility of this general approach to intravenous dosing and potential limitations of the method are discussed.

Notes: Abstract A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg iv bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine aminotransferase (TAT) mRNA, and TAT activity in liver were determined at various time points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45–50% of the baseline in 8–10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complex. A full PK/PD model for GR mRNA/GR down-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 hr, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1–2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.

Notes: Abstract The axial dispersion model of hepatic drug elimination is characterized by two dimensionless parameters, the dispersion number, DN , and the efficiency number, RN , corresponding to the relative dispersion of material on transit through the organ and the relative efficiency of elimination of drug by the organ, respectively. Optimal design theory was applied to the estimation of these two parameters based on changes in availability (F) of drug at steady state for the closed boundary condition model, with particular attention to variations in the fraction of drug unbound in the perfusate (fuB ). Sensitivity analysis indicates that precision in parameter estimation is greatest when F is low and that correlation between RN and DN is high, which is desirable for parameter estimation, when DN lies between 0.1 and 100. Optimal design points were obtained using D-optimization, taking into account the error variance model. If the error variance model is unknown, it is shown that choosing Poisson error model is reasonable. Furthermore, although not optimal, geometric spacing of fuB values is often reasonable and definitively superior to a uniform spacing strategy. In practice, the range of fuB available for selection may be limited by such practical considerations as assay sensitivity and acceptable concentration range of binding protein. Notwithstanding, optimal design theory provides a rational approach to precise parameter estimation.

Notes: Abstract Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax ) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration–time curve [AUC(0 → ∞ )] was 325 μg · hr ml and the mean elimination half-life (t1/2 ) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.

Notes: Abstract The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after iv bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.

Notes: Abstract Indirect response models require differential equations to describe the nonlinear inhibition or stimulation of the production or loss (kout ) of the response variable. Partially integrated solutions for these models developed previously for iv bolus or biphasic pharmacokinetics were extended to consider drug infusions for limited or extended durations. Qualitative examination was made of the role of infusion rate and duration, type and rate of drug disposition, Imax or Smax capacity factors, IC50 or SC50 sensitivity factors, and kout values. Properties of the response curves characterized include curve shapes, maximum or minimum response, onset rate, steady-state, and return to baseline. Some comparisons were made with behavior of iv bolus doses. These relationships provide both a formal and practical basis for better understanding of the time-course of basic indirect response models.

Notes: Abstract A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic–pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (μg/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and SigmoidEmax effect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlag ,ka , β,T1 / 2β ,AUC0–∞ ,Vd/F,andClp/F) were not different than those reported previously, except the APAPka was significantly lower. The link component yieldedkeo s of 0.58±0.06 (X±SE), 0.70±0.11 and 0.57 ± 0.11 hr -1 for APAP, IBU05, and IBU10, respectively: the SigmoidEmax component yieldedEC50 s (μg/ml) and sigmoidicity (γ) of 4.63±0.39 and 3.98±0.42 for APAP, 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10. On visual inspection of the efficacy–time profiles of the febrile children, a number of them had an apparent linear function (slope; Δ°C/hr) and/or a sinusoidal cyclic function “confounding” standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (Δ°C/hr) and/or a sinusoidal cyclic function to the SigmoidEmax component to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual Δ°Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBUAUC0–∞ was confirmed; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞ by only 1.5-fold. The confounding effect of initial temperature (Tempi ) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p=0.03) contribution ofTempi (but not age) on the value of the slope function was found. There was no consistent effect of age orTempi , on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age andTempi was observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, andTempi interacted with β in a significant multiple linear relationship withAUC0–∞ . The effects of IBU dose, age, andTempi are pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified SigmoidEMax effect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempi on the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition toTempi . A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.

Notes: Abstract Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on down-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR density, as well as tyrosine aminotransferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male adrenalectomized Wistar rats received MPL by iv injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Time 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free GR, GR mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK revealing low interindividual variation in CL and Vc values (3–14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Pharmacodynamic Response Model I (Model A) where the complex in the nucleus decreases the transcription rate of GR mRNA better described GR mRNA/GR down-regulation. Levels of TAT mRNA began to increase at 1–2 hr, reached a maximum at 5–6 hr, and declined to the baseline at 12–14 hr after MPL dosing. The induction of TAT activity followed a similar pattern with a delay of about 1–2 hr. The low-dose group had 50–60% of the TAT mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70% of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50–60% of the initial responses were produced. Our fourth-generation model describes the dose dependence and tolerance effects of TAT mRNA/TAT induction by MPL involving multiple-step signal transduction controlled by the steroid regimen, free GR density, and GR occupancy. This model may provide the foundation for studying other induced proteins or enzymes mediated by the similar receptor/nuclear events.

Notes: Abstract Direct pharmacologic effects are known to recede over time with largely linear slopes (Levy's k · m product, J. Pharm. Sci. 53: 342, 1964) and indirect responses have similar behavior. Pharmacodynamic slope properties were examined mathematically for the Hill function with monoexponential drug disposition and simulations were carried out for other pharmacokinetic functions. Both types of pharmacodynamic profiles exhibit a single terminal inflection point (fp) when drug concentrations exceed the EC50 (that concentration causing one-half maximum effect, Emax ). For direct effects it was found that Cfp (the drug concentration at fp) =EC50 , the determinants of inflection time were identified, and Slopefp = −λzγEmax /4 where λz is the terminal disposition slope and γ is the Hill coefficient. These characteristics were explored for the four basic indirect response models which also exhibit recession profiles with slight sigmoidity and a single terminal inflection point at higher doses. The drug concentration at inflection Cfp is ≤IC50 or SC50 (drug concentrations causing half-maximal inhibition or stimulation), while the inflection response (Rfp ) attains constant values at larger doses. Indirect Response Models I, III, and IV have nearly linear return slopes for a wide range of doses which are governed by the disposition slope λz of the drug, loss constant kout of the response, maximum inhibition (Imax ) or stimulation (Smax ) factors, and a unique fractional constant (0〈G≤1). Model II exhibits more complex behavior with recession slopes which are less likely to be parallel for various doses. Most indirect responses are expected to show nearly linear recession slopes which are parallel for moderate to large doses and mainly governed by an identical combination of pharmacokinetic (λz ), system (kout ), and dynamic capacity factors (Imax or Smax ).

Notes: Abstract Purpose. Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats. Methods. Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined. Results. The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine. Conclusions. The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration.

Notes: Abstract Purpose. This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities. Methods. In vitro dissolution — in vivo absorption analysis was conducted on four formulations of each ranitidine HC1, metoprolol tartrate, and piroxicam to yield apparent and "true” human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined. Results. In vitro dissolution — in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [k p = 0.225 hr−1, 0.609 hr−l, and 9.00 hr−1 for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine. Conclusions. There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.

Notes: Abstract Purpose. To apply cocktail approaches for protein binding (PB) and pharmacokinetics (PK) within a discovery program as a means of providing timely systemic exposure (AUC and Cmax) data. Methods. For PB data, a procedure of cocktail ultrafiltration, mixed matrix sample preparation and single quadrupole atmospheric pressure ionization LC/MS analysis was used. In vivo PK studies consisted of 4 experimental compounds and a control compound dosed orally at 1 mg/kg (5 mg/kg total dose), with plasma samples obtained at 0.5, 1, 2, 4 and 8 h post dose. For PB and in vivo PK analysis, a control compound was tested within each cocktail to ensure consistent reproducibility. Results. Approximately 2 weeks were spent comparing single and cocktail approaches to determine the feasibility of this method for this project. Comparisons of cocktail data with single compound data revealed no significant differences between the approaches. The oral AUC values ranged from 0.01 to 9.28 μg⋅hr/ml and the Cmax values ranged from 0.04 to 2.17 μg/ml. Free fractions of the 44 compounds studied ranged from 0.006 to 0.271. Using the free fraction values to correct for free AUC and Cmax results in ranges of 0.001 to 0.473 μg⋅hr/ml, and 0.001 to 0.119 μg/ml, respectively. Conclusions. All 44 compounds tested had similar potencies in vivo. Thus, these results suggest that a respective 400 and 100-fold range in AUC and Cmax corrected for free fraction exist in the presence of comparable in vivo activity. The ability to generate this type of data in a timely manner allowed the selection of a candidate with low peripheral exposure relative to the effective dose. The free fraction and PK data on the 44 compounds described was collected within three work days by 2 lab scientists.

Notes: Abstract Purpose. To elucidate the pharmacokinetics of amphotericin B in rats, mice and humans, and to perform interspecies scaling to humans using allometry. Methods. Plasma concentrations following intravenous bolus administration in rats, and mice were determined by HPLC. Human pharmacokinetic parameters elucidated from literature data were validated in a preliminary study involving a patient receiving daily infusion dose for 27 days. A critical literature review was conducted to identify appropriate pharmacokinetic parameter values in other species for interspecies scale-up. Interspecies allometric scale-up was performed across mice, rats, rabbits and dogs and the resulting predictions in humans were compared to observed values. Results. A triexponential decline in rat, mouse and human plasma concentrations were observed. No gender differences in rat pharmacokinetics were observed. In contrast to allometry, mouse CL was smaller (82 vs 116 ml/h/kg) and T0.5 (33 vs 20 h) was longer compared to rat. In the preliminary human study, Cpeak and Cmin values remained relatively constant over the duration of therapy, and a CL, MRT, T0.5, Vss and Vdarea of 26 ml/h/kg, 10 and 23 days, 6.2 and 20 L/kg, respectively, were estimated. The relative contributions of the terminal phase area in rat, mouse and human were 75%, 92% and 31%, respectively. Interspecies allometric scale-up predictions of human CL (41 ml/h/kg), CLu (467 ml/h/kg) and Vss (3.3 L/kg) were similar to reported values, whereas poor predictions of human Vuss (33 L/kg), Vdarea (4.1 L/kg) and T0.5 (3 days) were obtained. Conclusions. Insignificant accumulation in humans inspite of the long terminal T0.5 was rationalized to be due to the small terminal-phase area contribution. While human CL and Vss were sucessfully predicted in the interspecies scaling, poor predictions of human Vdarea and T0.5 were obtained, which was attributed to disposition pattern differences between humans and other species, a potential new critical factor affecting interspecies scale-up.

Notes: Abstract The immediate and long-term effects of the selective serotonergic neurotoxin 5,7-dihydroxytryp-tamine (5,7-DHT) on rat striatal serotonergic neurons were examined after its intracerebroventricular administration using in vivo voltammetry. Extracellular concentration of 5-hydroxyindoles increased immediately following intracerebroventricular 5,7-DHT injection (200 μg in 24 μl, 18 min), peaked at 1.5-2 h, and returned to normal by 4 h. 5,7-DHT diffused to the contralateral striatum in detectable amounts 9 to 12 min after the start of injection and returned to basal levels by 1.5 h. Three to 6 days after 5,7-DHT lesions, 5-hydroxytryptophan administration produced an increase in striatal 5-hydroxyindoles that was greater than that produced in pre-lesioned rats. This effect was maximal at 14 to 17 days post-lesion, and remained even after 50 days. The short-term effect of 5,7-DHT may be attributable to increased serotonin release, inhibition of uptake, or monoamine oxidase inhibition. The long-term effect of 5,7-DHT lesions may attributable to increased synthesis of serotonin or decreased reuptake in remaining serotonergic neurons.

Notes: Abstract: The paracetamol absorption technique, a widely used method for evaluating the gastric emptying rate of liquids, appears to be performed inappropriately, resulting from a lack of consideration of pharmacokinetics in paracetamol absorption. This review suggests that appropriate study designs and logical choice of the parameters for the rate of paracetamol absorption are the cornerstone of reliable investigation of gastric emptying using the paracetamol method.

Notes: Abstract We first recall the observational and theoretical facts that constitute the so-called 3He problem. We then review the chemical anomalies that could be related to the destruction of 3He in red giants stars. We show how a simple consistent mechanism can lead to the destruction of 3He in low mass stars and simultaneously account for the low 12C/13C ratios and low lithium abundances observed in giant stars of different populations. This process should both naturally account for the recent measurements of 3He/H in galactic HII regions and allow for high values of 3He observed in some planetary nebulae. We propose a simple statistical estimation of the fraction of stars that may be affected by this process.

Notes: To get informations on both the structure and dynamics of hydrogen chelates 1 of heteroaromatic systems, a great variety of quinazoline-2-acetonitrile chelates were synthesized (see 2-4). Similarly to the situation of the corresponding H-chelates in the pyrimidine-2-acetonitrile series, the investigation of these new derivatives 2-4 by NMR spectroscopic methods (DNMR, COSY, NOESY, ROESY, EXSY, HMQC, HMBC) confirms the presence of an equilibrium of the two possible H-chelate structures (two ‘rotamers’ I and II, i.e., (E)/(Z) isomers; see Scheme). The corresponding equilibria I ⇌ II were determined by complete 1H-NMR signal assignment at low temperatures (after freezing the rotational processes). In addition, the tautomer equilibria A ⇌ B (relative energies of the two minima of the nonsymmetrical double-well potential) for both ‘rotamers’ are ascertained by H,H and C,H couplings. The results are an important basis for the interpretation of both the UV/VIS absorptions and the dependence of fluorescence and fluorescence quantum yields on temperature.

Notes: Stereoselective reactions of phthalimido-substituted radicals derived from (±)-threonine with different radical traps are reported (Scheme 3, Table 1). A strong influence of the nature of the radical trap on the stereoselectivity was noticed. Small nucleophilic radical traps gave preferentially the syn products. The observed selectivities are explained with the A1,3 strain model and depend on steric and electronic effects (Fig. 2). Reactions with electrophilic radical traps such as diphenyl diselenide gave the anti diastereoisomers with moderate stereocontrol, presumably due to stereoelectronic effects. The same stereochemical outcome, i.e., preferential formation of the anti products, was observed for the reactions of the related N-phthaloyliminium ion (Scheme 5, Table 2). The stereochemistry of the ionic reaction is rationalized by a Felkin-Anh model (Fig. 3).

Notes: The cyclopalladation of 1,1′-azonaphthalene (= di(naphthalen-1-yl)diazene; 2) with bis(hexafluoroacetyl-acetonato)palladium(II) (3; [Pd(hfa)2]) yields the ortho-palladated complex (1,1,1,5,5,5-hexafluoropentane-2,4-dionato-κ2O,O′)[1-(naphthalen-1-ylazo-κN2)naphthalen-2-yl-κC2]palladium(II) (4) as well as the peri-palladated complex (1,1,1,5,5,5-hexafluoropentane-2,4-dionato-κ2O,O′)[8-(naphthalen-1-ylazo-κN2)naphthalen-1-yl-κC1]-palladium(II) (5); their structures were corroborated by X-ray analyses. The formation of the novel peri-metallated product 5 containing a six-membered palladacycle strongly depends upon the reaction conditions.

Notes: The photoisomerization behavior of three mono[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines, 1, 2, and 3, and three bis[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines, 4, 5, and 6, are investigated. The synthetic product (E)-1 could be almost quantitatively (〉 96%) converted into its isomer (Z)-1 under UV light irradiation. In the cases of (E)-2 and (E)-3, a mixture of (E)/(Z) ca. 1:2 was obtained, when the same conditions were applied. The comparison of their UV spectra provides the possible explanation for these different behaviors. Furthermore, it was noticed that the (Z) → (E) isomerization of the C=C bond took place during the purification by reverse-phase high-performance liquid chromatography (RP-HPLC), and the (E)/(Z)-mixture is thus inseparable. The same feature could be observed during the isolation of the (Z,Z)-N,N′-bis[3-(4-hydroxyphenyl)prop-2-enoyl]-spermidines, (Z,Z)-4, (Z,Z)-5, and (Z,Z)-6. Nevertheless, the fractions of (Z,Z)-5 and (Z,Z)-6 were in almost pure state collected, and their 1-NMR spectra are presented.

Notes: The synthesis, absolute configuration, and olfactive evaluation of (-)-(E)-α-trans-bergamotenone (= (-)-(1′S,6′R,E)-5-(2′,6′-dimethylbicyclo[3.1.1]hept-2′-en-6′-yl)pent-3-en-2-one; (-)-1), as well as its homologue (-)-19 are reperted. The previously arbitrarily attributed absolute configuration of 1 and of (-)-α-trans-bergamotene (= (-)-(1 S,6R)-2,6-dimethyl-6-(4-methylpent-3-enyl)bicyclo[3.1. 1]hept-2-ene; (-)-2), together with those of the structurally related aldehydes (-)-3a,b and alcohols (-)-4a,b, have been rigorously assigned.

Notes: (-)-(R)-4,4,4,4′,4′,4′-Hexafluorovaline hydrochloride ((R)-5) of 98% ee is prepared from β,β-bis(trifluoromethyl)acrylic acid (= benzyl 4,4,4-trifluoro-3-(trifluoromethyl)but-2-enoate; 1) in 4 steps with an overall yield of 9.6%. Key step is the separation of the TsOH salts of the diastereoisomers obtained by anti-Michael addition of (+)-(R)-1-phenylethylamine (2) to 1 (→ (R,R)-3). In contrast to the published (S)-chirality, the X-ray structure analysis of (R,S)-6 reveals, that (R)-chirality has to be assigned to the levorotatory (-)-4,4,4,4′,4′,4′-hexafluorovaline hydrochloride.

Notes: The synthesis and characterization of tripodal dodecadentate ligands with salicylamide and bipyridine binding sites for iron(II) and iron(III) are presented.

Notes: The reaction of CuO'Bu with CO2, and iPr2NH in the presence of PPh3, gives the dialkylcarbamato complex [Cu(O2CNiPr2)(PPh3)2] (1). The CO2/R2NH system (R = Me, Et) in an appropriate organic medium reacts with Ag2O giving the corresponding N,N-dialkylcarbamato complexes of analytical formula [Ag(C2CNR2)] (R = Me, 2; R = Et, 3). The methyl derivative 2 was characterized by X-ray diffraction methods. Crystal data of 2: for [Ag2(O2CNMe2)2], C6H12Ag2N2O4, mol. wt. 391.9; monoclinic, space group P21/c, a = 12.08(1), b = 3.797(2), c = 11.316(7) Å, β = 113.37(6)°, V = 476.3 Å3, Z = 2, Dc = 2.732 g cm-3; μ(MoKα) = 40.64 cm-1, F(000) = 376.0; R = 0.059, Rw = 0.067; g.o.f. 1.27. The structure consists of dinuclear [(Ag2OCNMe2)2] units with slightly distorted linearly two-coordinated Ag-atoms containing bridging carbamato groups to form a substantially planar eight-membered ring with an intra-annular Ag—Ag distance of 2.837(2) Å; the dinuclear units are further joined by Ag—O bonds to form an infinite array. Compound 3, which is presumably dinuclear, as suggested by cryoscopic measurements in benzene, undergoes a structural fission with PPh3, giving the mononuclear triphenylphosphine derivative [Ag(O2CNEt2)(PPh3)2] (4). The amine-catalyzed conversion of Ag2O into Ag2CO3, in the presence of the iPr2NH/CO2 system, is also reported. Cl-Exchange from [AuCl(PPh3)] with [Ag(O2CNEt2)] (3) gives the first N,N-dialkylcarbamato complex of gold, namely [Au(O2CNEt2)(PPh3)] (5), which crystallizes in the monoclinic system: C23H25AuNO2P · 0.5 C7H16, mol. wt. 625.5, space group P21/c; a = 13.212(5), b = 12.25(1), c = 16.795(6) Å, β = 109.09(2)°, V = 2568(2) Å3, Z = 4, Dc, = 1.618 g cm-3; μ(AgKα) = 31.40 cm-1, F(000) = 1236.0; R = 0.058; Rw = 0.064; g.o.f. 2.121. The compound contains two-coordinated Au-atom, namely to the P-atom and to the O-atom of the monodentate carbamato group, the P—Au—O bond angle being 174.7(3)°. The reaction with MeI showed these compounds to react predominantly at the carbamato O-atom giving the corresponding urethanes R2NCO2Me. Evidence was gathered for the transient coordination of CO to Ag in 3.

Notes: The reactions of α-diazo ketones 1a,b with 9H-fluorene-9-thione (2f) in THF at room temperature yielded the symmetrical 1,3-dithiolanes 7a,b, whereas 1b and 2,2,4,4-tetramethylcyclobutane-1,3-dithione (2d) in THF at 60° led to a mixture of two stereoisomeric 1,3-oxathiole derivatives cis- and trans-9a (Scheme 2). With 2-diazo-1,2-diphenylethanone (1c), thio ketones 2a-d as well as 1,3-thiazole-5(4H)-thione 2g reacted to give 1,3-oxathiole derivatives exclusively (Schemes 3 and 4). As the reactions with 1c were more sluggish than those with 1a,b, they were catalyzed either by the addition of LiClO4 or by Rh2(OAc)4. In the case of 2d in THF/LiClO4 at room temperature, a mixture of the monoadduct 4d and the stereoisomeric bis-adducts cis- and trans-9b was formed. Monoadduct 4d could be transformed to cis- and trans-9b by treatment with 1c in the presence of Rh2(OAc)4 (Scheme 4). Xanthione (2e) and 1c in THF at room temperature reacted only when catalyzed with Rh2(OAc)4, and, in contrast to the previous reactions, the benzoyl-substituted thiirane derivative 5a was the sole product (Scheme 4). Both types of reaction were observed with α-diazo amides 1d,e (Schemes 5-7). It is worth mentioning that formation of 1,3-oxathiole or thiirane is not only dependent on the type of the carbonyl compound 2 but also on the α-diazo amide. In the case of 1d and thioxocyclobutanone 2c in THF at room temperature, the primary cycloadduct 12 was the main product. Heating the mixture to 60°, 1,3-oxathiole 10d as well as the spirocyclic thiirane-carboxamide 11b were formed. Thiirane-carboxamides 11d-g were desulfurized with (Me2N)3P in THF at 60°, yielding the corresponding acrylamide derivatives (Scheme 7). All reactions are rationalized by a mechanism via initial formation of acyl-substituted thiocarbonyl ylides which undergo either a 1,5-dipolar electrocyclization to give 1,3-oxathiole derivatives or a 1,3-dipolar electrocyclization to yield thiiranes. Only in the case of the most reactive 9H-fluorene-9-thione (2f) is the thiocarbonyl ylide trapped by a second molecule of 2f to give 1,3-dithiolane derivatives by a 1,3-dipolar cycloaddition.

Notes: The synthesis of a series of chiral enantiomerically pure C2-symmetric binucleating ligands is reported. Ligands of type 1-4, which consist of a phenolic or heterocyclic unit bridging two chiral dihydrooxazole rings. are readily accessible from chiral amino alcohols. Ligands 5a and 5b are composed of a cyclic urea or thiourea unit, respectively, and two 3,4-dihydro-2H-pyrrole rings containing a stereogenic center next to the N-atom. Compounds of this type are readily assembled from ethane-1,2-diamine and an imidothioic ester derived from pyroglutamic acid. These new ligands, which can coordinate two metals in close proximity to each other, are of interest regarding possible applications in asymmetric catalysis.

Notes: Stability constants have been measured for a series of ligands based on a 2,2′-(pyridine-2,6-diyl)bis[1H-benzimidazole] unit which forms dinuclear double-stranded helical complexes with copper(I). Variation of different structural parameters confirms the importance of the coordinate bond, the stacking interactions, and the weakly bridging pyridine units observed by X-ray crystallography. The stabilities of the complexes depend strongly on the solvent, and in MeCN, which is a good solvent for copper(I), the complexes are less stable and assemble in a stepwise manner. The interconversion of the enantiomers may be followed by 1H-NMR and takes place on a millisecond time scale around room temperature. The trends in lability are similar to those found for the stability of the complexes.

Notes: Oligodeoxyribonucleotides containing 7-deaza-2′-deoxy-8-methylguanosine (m8c7Gd; 2b) were prepared. For this purpose, the phosphonate 3a and the phosphoramidite 3b were synthesized and employed in solidphase oligodeoxyribonucleotide synthesis. The structures and the thermodynamic data of duplex formation of oligodeoxyribonucleotides containing 2b were investigated by temperature-dependent CD and UV spectra and compared with those containing 7-deaza-2′-deoxy-7-methylguanosine (m7c7Gd) or 7-deaza-2′-deoxy-guanosine (c7Gd; 2a). In general, compound 2b reduces the duplex stability. In case of the sequence d(m8c7G-C)4 (18), the B → Z transition was facilitated by the incorporation of 2b. Moreover, a single 7-deaza-8-methylguanine residue present in an oligodeoxyribonucleotide tract of guanine residues destabilizes the dG quadruplex significantly. This destabilization is more pronounced than in the case of 7-deazaguanine or 7-deaza-7-methyl-guanine.

Notes: Absolute rate constants and their Arrhenius parameters are obtained for the addition of a cyclic malonyl radical derived from Meldrum's acid to 20 mono- or 1,1-disubstituted alkenes in (±)-propylene oxide and for the addition of the open-chain di(tert-butyl)malonyl radical to six mono- or 1,1-disubstituted alkenes in 1,1,2-trichloro-1,2,2-trifluoroethane by time-resolved electron spin resonance spectroscopy. At room temperature, the radicals add at the unsubstituted C-atoms with rate constants ranging from 1.1. 105 M-1S-1 (acrolein) to 2.4. 106 M-1S-1 (1,1-diphenylethene). The frequency factors are in the narrow ranges of log (A/M-1S-1) = 8.7 ± 0.1 for the cyclic and log (A/M-1S-1) = 8.2 ± 0.2 for the open-chain malonyl species, whereas the activation energies vary from 12.9 kJ/mol (1,1-diphenylethene) to 21.7 kJ/mol (acrylonitrile). They correlate with the alkene ionization potentials and, more weakly, with the reaction enthalpy. No correlation was found between the activation energies and the alkene electron affinities. Hence, the results confirm and quantify the electrophilic nature of malonyl radicals in addition reactions.

Notes: An asymmetric synthesis of (-)-(4R)-dihydroisomyricoidine (28), a 13-membered amino lactam of type A, was performed by a diastereoselective Michael addition between the spermidine derivative 3 and the commercially available optically active ethyl carboxylate 4, and the cyclization of the resulting ω-amino acid 7 using diethyl phosphorocyanidate ((EtO)2POCN), followed by a Wittig reaction to introduce the (Z)-side chain. Some side reactions are also discussed.

Notes: Natural free carboxylic acids from the hadromerid sponge Diacarnus levii (Kelly-Borges and Vacelet) were esterified to yield the new cyclic norditerpene peroxides ent-muqubilin benzyl ester (= (αR,3S,6R)-α,6-dimethyl-6-[(E)-4-methyl-6-(2,6,6-trimethyl-cyclohex-1-en-1-yl)hex-3-enyl]-1,2-dioxan-3-acetic acid benzyl ester; 6, diacarnoate B methyl ester(= (αS,3R,6R)-α,6-dimethyl-6-{2-(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-3-oxo-2,5,5,8a-tetramethylnaphthalen-1-yl)ethyl}-1,2-dioxan-3-acetic acid methyl ester; 9), and deoxydiacarnoate B benzyl ester (= (αS,3R,6R)-α,6-dimethyl-6-{2-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethyl-1-naphthalenyl]ethyl}-1,2-dioxan-3-acetic acid benzyl ester; 10), which were isolated following extensive chromatography. The relative configuration of the peroxide/α-methylacetate moiety of 6, 9, and 10, was directly determined from their NMR spectra. The absolute configurations of the peroxide/α-methylacetate moiety was deduced from comparative 1H-NMR data of the (S)- and (R)-phenylglycine methyl ester derivatives 7 and 8 as well as 11/13 and 12/14, all obtained from a mixture of the precursors of 3, 6, and 10. The absolute configuration at the carbobicyclic moiety of enone 9 and of 10, is identical, as established by chemical interconversion, 9 and 10 belong to the normal labdane series according to empirical CD rules, applied either directly to 9 or to the parent (+)-sclareolide-derived enone 20. In contrast, molar rotation additivity rules suggest the ent-labdane configuration for 9 and 10. The epidioxides 1-3, 6, and 10 proved active in vitro against the malaria parasite Plasmodium falciparum; especially the previously isolated methyl 3-epinuapapuanoate (2) was active against a chloroquine-resistant strain, and this with a good security index.

Notes: 3-Hydroxy-2-cyanoalk-2-enamides, and 2-cyano-2-(tetrahydrofuran-2-ylidene)- and 2-cyano-2-(tetrahydropyran-2-ylidene)acetamides with N-alkyl and N-aryl substituents have been synthesized in three steps from cyanoacetic acid. Their conformations were investigated by X-ray crystallography and 1H-NMR ROESY spectroscopy at room temperature. The enolic compounds 1-3 adopt an extended conformation stabilized by a strong intramolecular O—H … O=C bond both in the solid state and in (D6)DMSO solution. In contrast, the structure of the cyclic derivatives 5a,b-8a,b is solvent-dependent. In the solid state and in CDCl3 solution, the compounds adopt an extended conformation of type I or III, while, in (D6)DMSO solution, their structures undergo time-dependent (Z)/(E)-isomerization structures (of type II or IV). This observation is compatible with a dipolar transition state of rotation. The kinetics of the isomerization are controlled by the N-substituent, the N-(t-Bu) derivatives 7a and 7b having the highest barrier of rotation around the C=C bond. The whole body of experimental evidence together with the results of molecular-mechanics calculations with I-IV, indicate that, in DMSO, two (E)/(Z)-isomers with two conformations are present, and that they undergo interconversion at room temperature with four different constants. The very fast exchange rates kI,II and kIII,IV in the NMR time-scale might be responsible for the detection of only two isomers.

Notes: A new acylated dimeric secoiridoid glycoside, seemannoside A (2), has been isolated from the aerial parts of Lisianthius seemannii (GRISEB) O. KUNTZE (Gentianaceae). The structure was established by spectroscopic analysis (UV, MS, 1H- and 13C-NMR, and 2D-NMR experiments) and chemical reactions as (E-4′-O-p-coumaroyl)lisianthioside. The structure of the (Z)-isomer (seemannoside B, 3), also present in the plant, was confirmed by LC/UV/1H-NMR analysis. The active principle, 6, responsible for the antifungal activity of the apolar extract against Cladosporium cucumerinum, has been isolated. Its structure has been established by NMR spectroscopy and X-ray crystallographic analysis as a rare type of aglycone monoterpene dimer.

Notes: Asymmetric Diels-Alder reaction of the pentadienoic and hexadienoic acids 2a,b with the chiral chloronitroso derivative 3 gave the primary adducts 4a,b with good-to-excellent enantioselectivity. Subsequent as- or trans-dihydroxylation and hydrogenolytic cleavage of the N—O bond led to the 5-amino-5-deoxypentono-δ-lactams 13a, 14, 15a, and 16 in the D-ribose, L-arabinose, D-xylose, and L-lyxose series, respectively, and to the 5-amino-5,6-dideoxyhexono-δ-lactams 13b and 15b in the D-allose and D-glucose series, respectively.

Notes: The synthesis of the monomeric building block 13 and its constitutional isomer 12 of a new type of DNA analog, distamycin-NA, is presented (Schemes 1 and 2). This building block consists of a uracil base attached to a thiophene core unit via a biaryl-like axis. Next to the biaryl-like axis on the thiophene chromophore, a carboxy and an amino substituent are located allowing for oligomerization via peptide coupling. The proof of constitution and the conformational preferences about the biaryl-like axis were established by means of X-ray analyses of the corresponding nitro derivatives 10 and 11. Thus, the uracil bases are propeller-twisted relative to the thiophene core, and bidentate H-bonds occur between two uracil bases in the crystals. The two amino-acid building blocks 12 and 13 were coupled to give the dimers 15 and 16 using dicyclohexylcarbodiimide (DCC) in THF/LiCl and DMF, respectively. While the dimer 15 showed no atropisomerism on the NMR time scale at room temperature, its isomer 16 occurred as distinct diastereoisomers due to the hindered rotation around its biaryl-like axis. Variable-temperature 1H-NMR experiments allowed to determine a rotational barrier of 19 ± 1 kcal/mol in 16. The experimental data were complemented by AM1 calculations.

Notes: Heating of a mixture of N,N′-(thiocarbonyl)diimidazole (= 1,1′-(carbonothioyl)bis[1H-imidazole]; 1) and 2,5-dihydro-1,3,4-thiadiazole 2a or 2b gave the 1,3-dithiolanes 4a and 4b, respectively, via a regiospecific 1,3-dipolar cycloaddition of the corresponding ‘thiocarbonyl methanides’ 3a,b onto the C=S group of 1 (Schemes 1 and 2). The adamantane derivative 4b was not stable in the presence of 1H-imidazole and during chromatographic workup. The isolated 1,3-dithiole 5 is the product of a base-catalyzed elimination of 1H-imidazole from the initial cycloadduct 4b. The formation of the S,N-acetal 6 can be rationalized by a protonation of the ‘thiocarbonyl ylide’ 3b followed by a nucleophilic addition of 1H-imidazole. With the diazo compounds 8a-e (Scheme 3) 1 underwent a regiospecific 1,3-dipolar cycloaddition to give the corresponding 2,5-dihydro-1,3,4-thiadiazole derivatives 9, which spontaneously eliminated 1H-imidazole to yield (1H-imidazol-1-yl)-1,3,4-thiadiazoles 10. The structures of 10a and 10d were established by X-ray crystallography. In the case of diazodiphenylmethane (8f), the initial cycloadduct 9f decomposed via a ‘twofold extrusion’ of N2 and S to give 1,1′-(2,2-diphenylethenylidene)bis[1H-imidazole] (11; Scheme 3).

Notes: The synthesis of new deoxyribose nucleosides by coupling chloropurines with modified D-ribose derivatives is reported. The methyl 2-deoxy-N-methyl-3-O-(p-toluoyl)-α-D-ribofuranosiduronamide (α-D-8) and the corresponding anomer β-D-8 were synthesized starting from the commercially available 2-deoxy-D-ribose (1) (Scheme 1). Reaction of α-D-8 with the silylated derivative of 2,6-dichloro-9H-purine (9) afforded regioselectively the N9-(2′-deoxyribonucleoside) 10 as anomeric mixture (Scheme 2), whereas β-D-8 did not react. Glycosylation of 9 or of 6-chloro-9H-purine (17) with 1,2-di-O-acetyl-3-deoxy-N-methyl-β-D-ribofuranuronamide (13) yielded only the protected β-D-anomers 14 and 18, respectively (Scheme 3). Subsequent deacetylation and dechlorination afforded the desired nucleosides β-D-11, β-D-12,15, and 16. The 3′-deoxy-2-chloroadenosine derivative 15 showed the highest affinity and selectivity for adenotin binding site vs. A1 and A2A adenosine receptor subtypes.

Notes: (S)-5,5,5,5′,5′,5′-Hexafluoroleucine ((S)-13) of 81 % ee is prepared from hexafluoroacetone (l) and ethyl bromopyruvate (= ethyl 2-oxopropanoate) in 7 steps with an overall yield of 18% (Schemes 1 and 2). Key step in this sequence is the highly enantioselective reduction of the carbonyl group in α-keto ester 4 either by bakers' yeast (91 % ee) or by ‘catecholborane’ 6 utilizing an oxazaborolidine catalyst, yielding hydroxy ester (R)-5 with 99% ee. The absolute configuration was determined by X-ray analysis of the HCl adduct (S,R)-9b of (2S)-N-[(R)- l-phenylethyl]-5,5,5,5′,5′,5′-hexafluoroleucine ethyl ester.

Notes: N-Fmoc-Protected (Fmoc = (9H-fluoren-9-ylmethoxy)carbonyl) β-amino acids are required for an efficient synthesis of β-oligopeptides on solid support. Enantiomerically pure Fmoc-β3-amino acids β3: side chain and NH2 at C(3)(= C(β)) were prepared from Fmoc-protected (S)- and (R)-α-amino acids with aliphatic, aromatic, and functionalized side chains, using the standard or an optimized Arndt-Eistert reaction sequence. Fmoc-β2- Amino acids (β2 side chain at C(2), NH2 at C(3)(= C(β))) configuration bearing the side chain of Ala, Val, Leu, and Phe were synthesized via the Evans' chiral auxiliary methodology. The target β3-heptapeptides 5-8, a β3- pentadecapeptide 9 and a β2-heptapeptide 10 were synthesized on a manual solid-phase synthesis apparatus using conventional solid-phase peptide synthesis procedures (Scheme 3). In the case of β3-peptides, two methods were used to anchor the first β-amino acid: esterification of the ortho-chlorotrityl chloride resin with the first Fmoc-β-amino acid 2 (Method I, Scheme 2) or acylation of the 4-(benzyloxy)benzyl alcohol resin (Wang resin) with the ketene intermediates from the Wolff rearrangement of amino-acid-derived diazo ketone 1 (Method II, Scheme 2). The former technique provided better results, as exemplified by the synthesis of the heptapeptides 5 and 6 (Table 2). The intermediate from the Wolff rearrangement of diazo ketones 1 was also used for sequential peptide-bond formation on solid support (synthesis of the tetrapeptides 11 and 12). The CD spectra of the β2- and β3-peptides 5, 9, and 10 show the typical pattern previously assigned to an (M) 31 helical secondary structure (Fig.). The most intense CD absorption was observed with the pentadecapeptide 9 (strong broad negative Cotton effect at ca. 213 nm); compared to the analogous heptapeptide 5, this corresponds to a 2.5 fold increase in the molar ellipticity per residue!

Notes: On irradiation (350 nm) in the presence of excess 2,3-dimethylbut-2-ene, the newly synthesized title compound 5 affords as main products the unexpected cyclopropylpyrrolidine 10 (50%) and the spiro-oxetane 9 (25%).

Notes: Among seventeen different Lewis acids, TiCl4 was found to be the best catalyst for the [4 + 2] cycloaddition of cyclopentadiene to N,N′-fumaroylbis[(2R)-bornane-10,2-sultam] ((-)-1). Independently of the TiCl4 molar concentration, almost constant and complete (98-89% d.e.) diastereofacial π-selection was achieved in the Diels-Alder addition of (-)-1 to cyclopentadiene, cyclohexadiene, isoprene, and 2,3-dimethylbuta-1,3-diene.

Notes: A new facile synthesis of N,S- and N,Se-acetals starting from aldehydes and primary amines is presented (Schemes 3-5). These acetals are used as precursors for stereoselective radical deuteration and allylation reactions (Schemes 6 and 7, Tables 1 and 2). The stereochemical outcome of the reactions depends on the radical trap and the substituents at the N-atom. Deuterations give always anti products with moderate to high selectivities. The allylation reactions give either syn or anti products with low to moderate selectivities. The observed stereoselectivities can be explained with a model based on minimization of A1,3 strain and are controlled by steric and stereoelectronic effects.

Notes: Based on O-methylasparvenone (1), a N-free 5HT2C antagonist with moderate affinity (pKi = 6.7), derivatives bearing dimethylamino (7), (dimethylamino)methyl (17, 18, 21, and 22), and aminomethyl substituents (26) in place of the benzylic OH group of 1 as well as pyrrolidine- (33) and piperidine-fused derivatives (29, 43, and 45) were synthesized. In contrast to the lead structure 1, these new ligands were active in vivo in the rat. The tricycles 33 and 45 display high affinities for the 5HT2C receptor (pKi = 8).

Notes: Thermal reactions of 1,2,3-trisubstituted aziridines 1 with 1,3-thiazole-5(4H)-thiones 6 in toluene yielded, in general, a mixture of two diastereoisomeric spirocyclic [2+3] cycloadducts. The formation of these products can be explained by a stereoselective electrocyclic ring opening of 1 to give an azomethine ylide 2 as the reactive intermediate, which is trapped immediately by 6 via a stereoselective 1,3-dipolar cycloaddition. Only in the case of trans-dimethyl 1-(4-methoxyphenyl)aziridine-2,3-dicarboxylate (trans-1a), four diastereoisomeric cycloadducts were formed (Scheme 4). This result is rationalized by an isomerization of the intermediate azomethine ylide cis-2a to trans -2a.

Notes: Due to their small mass, adjacent protons (or H-atoms) of molecular systems may exhibit quantum entanglement (or quantum correlations), even at ambient conditions. The considerable thermal disturbance and/or manybody interactions of condensed matter and the associated decoherence effect, however, cause this protonic entanglement to be restricted in space and time. Some aspects of entanglement and decoherence are mentioned. Extending our previous theoretical work, in the present paper the focus is on the possible existence of entangled protons belonging to the H-bonds of adjacent base pairs of B-type DNA. Based on the ‘working hypothesis’ that this effect does really exist, the most probable ‘positions’ for the appearance of protonic entanglement in DNA sequences are qualitatively determined. Furthermore, these ‘positions’ appear to correspond uniquely to dimers of adjacent base pairs of DNA. As a consequence, one can straightforwardly search for an enhanced appearance of such entangled H-bonds in DNA sequences of living organisms, using the existing DNA databases. A quantitative analysis of protein-coding DNA sequences of various organisms has been performed, the results of which provide strong evidence for the existence of the considered effect. The most striking finding may be summarized as follows: Quantum entanglement appears preferably between the third base of a codon and the first base of the following one. Quantitative estimates of this and further obtained results are presented. It is also shown that quantum-chemical considerations of stacking energies cannot account for the results. The new findings provide first evidence for the biological significance of entangled H-bonds.

Notes: The title compounds D-10 and L-10 were prepared from 1 in eight steps and in a combined overall yield of 41-49%.

Notes: The reaction of N,N'-dimethyl-2-nitroethene-1,1-diamine (8) with α,ß-unsaturated acyl isothiocyanates 9 affords 3,3-diamino-2-nitroacrylthioamides 10 (Scheme 2) in moderate-to-good yields. Cyclization of 10 under acidic conditions gives 1,3-thiazin-4-one derivatives of type 11. Oxidative cyclization of 10 with diethyl azodicaboxylate leads to 4-nitro-1,2-thiazol-5(2H)-imine derivatives 12.

Notes: The CH2Cl2 extract of Monotes engleri Gilg. (Dipterocarpaceae) showed antifungal activity against the yeast Candida albicans in our bioautographic TLC assays. After a first fractionation of the crude extract, the bioactivity was located in one of the fractions. To perform an efficient targeted isolation of the active compounds, LC/UV/MS and LC/UV/NMR analyses of the crude extract and the active fraction were performed. LC/UV/, LC/MS, and LC/NMR data (1D and 2D) allowed the identification of 1 as (2S)-2,3-dihydro-5,7-dihydroxy-{3-hydroxy-4-[(3-methylbut-2-enyl) oxy]phenyl}-4H-1-benzopyran-4-one, a new prenylated flavanone, named monoteson A. Subsequent isolation of 1 has permitted the determination of its absolute configuration on the basis of CD measurements. Theree other prenylated flavanoes 2-4 were isolated from the same extract. Compound 3 was identified as 2- (3, 5-dihydroxyphenyl) -2,3-dihydro-5, 7-dihydroxy-6, 8-bis (3-methylbut-2-enyl)-4 H-1-benzopyran-4-one, another new natural product, named monotesone B. The structures of 2 and 4 were established as selinone and lonchocarpol A, respectively. The antifungal activity against Candida albicans was determined for all compounds.

Notes: The disubstituted clusters[Ir4(CO)10(μ2-L—L)] with one edge-bridging ligand have a ground-state geometry with all COs terminal (L—L = (MeS)2CHMe, cluster 1) or with three edge-bridging COs (L—L = (Ph2P)2CHMe, cluste 2; L—L =Ph2P(CH2)3PPh2, cluster 3) in the solid state and in solution. A comparative 13C-NMR study of 1-3 shows that their respective ground-state geometries are merely relative minima of energy in the same kinetic profile of successive fluxional processes consisting of a merry-go-round of six COs about a unique trangular face and the rotation of terminal COs about one Ir-atom. The factors affecting the activation energy of the merry-go-round result from the relative bites of the bidentate ligands in the ground-state geometry, as shown by a comparison of the molecular structures of 2 and 3.

Notes: The kinetics of the reaction between pyridoxal 5′-phosphate (PLP) with carbidopa, hydralazine, and isoniazid, in aqueous solution at variable pH and constant ionic strength of 0.1M was studied spectrophotometrically. The rate constants of formation and hydrolysis of the resulting Schiff base, and its stability were determined in a wide range of pH. A comparison is made of the formation rate constants with those of PLP with hydrazine. The reactivity shows the sequence isoniazid 〉 hydrazine 〉 carbidopa 〉 hydralazine in the whole range of pH studied. The Schiff bases studied are more stable than those formed by PLP and hexylamine and as stable as those described for the reactions of PLP with poly(L-lysine) or copolypeptides containing L-lysine.

Notes: The coordination behavior of chiral binucleating ligands of type 1-4 with various transition metals has been investigated. 1H-NMR Titration experiments with zinc(II) salts gave detailed structural information about the structure of the resulting zinc complexes. Ligand 1 forms an unusual C3-symmetric dinuclear zinc complex [Zn2CIL3] (8a) which was characterized by X-ray crystallography. Treatment of complex 8a with various carboxylic acids resulted in ligand-exchange reactions. With ligand 2, a hydroxo-bridged dinuclear copper complex 15 was synthesized and its structure elucidated by X-ray analysis. Solution studies UV and 1H-NMR spectroscopy of the reaction of ligand 3 with ZnII and NII salts revealed the formation of dimeric species of the type [M2X4L2]. Ligand 4 formed well-defined dinuclear complexes with NiII and CuII salts of which the corresponding NiII complex [Ni2(AcO)2(ClO4)2L] (22a) was characterized by crystal-structure analysis.

Notes: Why Pentose- and Not Hexose-Nucleic Acids? Purine-Purine Pairing in homo-DNA: Guanine,Isoguanine, 2,6-Diaminopurine, and XanthineThis paper concludes the series of reports in this journal [1-4] on the chemistry of homo-DNA, the constitutionally simplifie dmodel system of hexopyranosyl-(6′ → 4′)-oligonucleotide systems stidued in our laboratory as potentially natural-nucleic-acid alternatives in the context of a chemical aetiology of nucleic-acid structure. The report describes the synthesis and pairing properties of homo-DNA oligonucleotides which contain as nucleobases exclusively purines, and gives, together with part III of the series [3], a survey of what we know today about purine-purine pairingin homo-DNA. In addition, the paper discusses those aspects of the chemistry of homo-DNA which, we think, influence the way how some of the structural features of DNA (and RNA) are to be interpreted on a qualitative level.Purine-purine pairing occurs in the homo-DNA domain in great variety. Most prominent is a novel tridentate Watson-Crick pair between guanine and isoguanine, as well as one between 2,6-diaminopurine and xanthinone, both giving rise to very stable duplexes containing the all-purine strands in antiparallel orientation. For the guanine-isoguanine pair, constitutional assignment is based on temperature-dependent UV and CD spectroscopy of various guanine- and isoguanine-containg duplexes in comparison with duplexes known to be paired in the reverse guanine is replaced by 7-carbauguanine. Isoguanine and 2,6-diaminopurine also have the capability of self-pariring in the reverse-Hoogsteen mode, as previously observed for adenine and guanine [3]. In this type of pairing, the interchangeably. Fig. 36 provides an overall survey of the relative strength of pairing in all possible purine-purine combinations.Watson-Crick pairing of isoguanine with guanine demands the former to participate in its 3H-tautomeric form; hitherto this specific tautomer had not been considered in the pairing chemistry of isoguanine. Whereas (cumulative) purine-purine pairing in DNA (reverse-Hoogsten or Hoogsteen) seems to occur in triplexes and tetrapalexes only, its occurrence in duplexes in a characteristic feature of homo-DNA chemistry. The occurrence of purine-purine Watson-Crick base pairs is probably a consequence of homo-DNA's quasi-linear ladder structure [1][4]. In a double helix, the distance between the two sugar C-atoms, on which a base pair is anchored, is expected to be constrained by the dimensions of the helix; in a linear duplex, however, there would be no restrictions with regard to base-pair length. Homo-DNA's ladder-like model also allows one to recognize one of the reasons why nucleic-acid duplexes prefer to pair in antiparallel, rather than parallel strand orientation: in homo-DNA duplexes, (averaged) backbone and base pair axes are strongly inclined toward one another [4]; the stronger this inclination, the higher the preference for antiparallel strand orientation is expected to be (Fig. 16).In retrospect, homo-DNA turns out to be one of the first artificial oligonucleotide systems (cf. Footnote 65) to demonstrate in a comprehensive way that informational base pairing involving purines and pyrimidines is not a capability unique to ribofuranosyl systems. Stability and helical shape of pairing complexes are not necessary conditions of one another; it is the potential for extensive conformational cooperativity of hte backbone structure with respect to the constellational demands of base pairing and base stacking that determines whether or nor a given type of base-carrying backbone structure is an informational pairing system. From the viewpoint of the chemical aetiology of nucleic-acid structure, which inspired our investigations on hexopyranosyl-(6′ → 4′)-oligonucleotide systems in the first place, the work on homo-DNA is only an extensive model study, because homo-DNA is not to be considered a potential natural-nucleic-acid altenratie. In retrospect, it seems fortunate that the model study was carried out, because without it we could hardly have comprehended the pairing behavior of the proper nucleic-acid alternatives which we have studied later and which will be discussed in Part VI of this series.The English footnotes to Fig. 1-49 provide an extension of this summary.

Notes: ‘Fully chiral’ dendrimers, containing a stereogenic center at each and every branching point, have been prepared using a chiral core triol with aromatic elongating units (cf. 27) and chiral branch diols (cf. 8, 12, and 24) as building blocks. The biggest dendrimer prepared is of the 4th generation (33: 46 building blocks, 93 stereogenic centers, 1028 possible stereoisomers), and has been obtained by a convergent growth approach in 32 steps starting from the biopolymer poly[(R)-3-hydroxybutanoic acid] (P(3-HB)). All compounds were shown to be monodisperse by MALDI-TOF mass spectrometry. Spin-lattice relaxation-time (T1) measurements and size-exclusion chromatography show typical features of structurally related achiral dendrimers. The influence of the chiral building blocks on the shape of the whole dendrimer has been investigated by chiroptical measurements: the specific rotation can be considered as average of all chiroptical properties of its constituent chiral units, independent of the solvent, the concentration, and the temperature. On the other hand, regularity in the circular dichroism (CD) spectra is completely lost with variation of the solvent (cf. Fig. 13).

Notes: The first steps, believed to be involved in the highly enantioselective copolymerization of styrene and carbon monoxide to poly[1-oxo-2-phenylpropane-1,3-diyl] with phosphinodihydrooxazole-palladium(II) complexes, were investigated. The insertion of carbon monoxide into [Pd(Me)(P^N)(solvent)] TfO (P^N = (S)-2-[2-(5H-benzo[b]phosphindol-5-yl)phenyl]4-benzyl-4,5-dihydrooxazole (1)) and of styrene into [Pd(Me)(P^N)(solvent)] TfO were highly regioselective (alkyl and acyl substituents trans to N); moreover, the olefin insertion took place with essentially complete enantioface discrimination.

Notes: The [4 + 2] cycloadduct 17 of 2,3-dimethylidene-1,2,3,4-tetrahydro-1,4-methanonaphthalene and 4-phenyl-4H-1,2,4-triazole-3,5-dione (PTAD) was subjected to a triplet-sensitized di-π-methane rearrangement. Hydrolysis of the resulting urazol 18 gave the hydrocarbon 7. Hydrolysis of 18 at lower base concentrations led to isomeric stable semicarbazides 24 and 25, which were submitted NiO2 or MnO2 oxidation, to give the target compound 7, and oxidation products 26 and 27.

Notes: The difference between the strong inhibition of retaining β-glucosidases by the tetrazole 1 and the weak inhibition by the triazole 3 has been explained by the protonation by the enzymic catalytic acid of N(3) of 1, replaced by CH in 3. One also expects a contribution to the inhibition from the charge-dipole interaction between the enzymic catalytic nucleophile and the azole ring. The extent of this contribution was estimated from the calculated, distance-dependent heats of formation of the acetate-azole complexes. The calculations were validated by comparison of the charge-dipole interaction between phosphate and the inhibitors 1 and 3 in the glycogen phosphorylase b (GPb)-azole-phosphate complexes, as derived from differences in the Ki values for 1 and 3, while the structural invariance of the complexes was demonstrated by X-ray analysis. The difference between the charge-dipole interactions of (dihydrogen) phosphate and 1 or 3 as derived from Δ Ki is 1.1 kcal mol-1, while the calculated difference is 1.3 kcal mol-1. The calculated difference for the interaction of 1 or 3 with acetate, representing the catalytic nucleophile in β-glycosidases, is 2.0 kcal mol-1, while the differences of the binding energies as derived from the Ki values for the inhibition by 1 or 3 of different β-glycosidases range from 2.4 to 5.3 5 kcal mol-1. The calculated difference for 1 and the imidazole 6 is 2.5 kcal mol-1 in favour of 1, whereas the Ki-derived difference is 3.7 kcal mol-1 in favour of 6, equal to the calculated difference between 1 and the protonated imidazole 6. Thus, protonation by the catalytic acid and the charge-dipole interaction with the catalytic nucleophile contribute cooperatively to the binding of inhibitors possessing a trigonal anomeric centre bonded to a heteroatom.

Notes: Described are the preparation of nanocrystals and the synthesis of molecules that may be covalently or noncovalently assembled in solution to yield heterosupermolecules possessing a well-defined heterosupramolecular function. Also described are preparative and synthetic methods that yield organized assemblies of heterosupermolecules possessing an addressable heterosupramolecular function. Finally, the development of these synthetic strategies to permit the covalent and noncovalent assembly and organization of a wide range of condensed phase and molecular components is outlined.

Notes: For a comparison with the corresponding α- and β-hexapeptides H-(Val-Ala-Leu)2-OH (A) and H-(β-HVal-β-HAla-β-HLeu)2-OH (B), we have now prepared the corresponding γ-hexapeptide 1 built from the homochirally similar (S)-4-aminobutanoic acid, (R)-4-amino-5-methylhexanoic acid, and (R)-4-amino-6-methylheptanoic acid. The precursors were prepared either by double Arndt-Eistert homologation of the protected amino acids Boc-Val-OH, Boc-Ala-OH, and Boc-Leu-OH (Schemes 1 and 2), or by the superior route involving olefination/hydrogenation of the corresponding aldehydes (Boc-valinal, Boc-alaninal, and Boc-leucinal; Scheme 3). Conventional peptide-coupling methodology (EDC/HOBt) furnished the γ-hexapeptide 1 (through the intermediate γ-di- and γ-tripeptide derivatives 9-11). Analysis of NMR measurements in (D5)pyridine and CD3OH solution (COSY, TOCSY, HSQC, HMBC, ROESY) reveals that the γ-hexapeptide 1 adopts a right-handed helical structure ((P)-2.61 helix of ca. 5-Å pitch, containing 14-membered H-bonded rings) which is to be compared with the left-handed helix of the corresponding β-peptide B ((M)-31 helix of 5-Å pitch, 14-membered H-bonded rings) and with the familiar right-handed, so-called α-helix of α-peptides ((P)-3.61 helix of 5.4-Å pitch, 13-membered rings). Like the helix sense, the helix dipole reverses when going from α-, (N + → C) to β-(C + → N) to γ-peptides (N + → C). The surprising difference between the natural α-, and the analogous β- and γ-peptides is that the helix stability increases upon homologation of the residues.

Notes: 7-O-Substituted analogs of deaminodeoxycolchinol thiomethyl ether were synthesized and evaluated for their inhibitory effects on tubulin polymerization in vitro. Ketone 9, a key compound in this study, was derived from thiocolchicone 6 by reaction with aniline. Reaction of compound 6 with MeNH2 or BuNH2 gave tetracyclic lactams 7 and 8, respectively. Optically active alcohols 11a and 11b were obtained from racemic 11 by chemical resolution including a separation of the comphanate diastereoisomers 12a and 12b, followed by basic hydrolysis. The (aR,7R)-configuration of 12b was verified by X-ray crystallographic analysis. Almost all racemic and optically active 7-O-acyl or 7-O-aroyl compounds had strong inhibitory effects on the tubulin polymerization reaction, with IC50 values from 1.7 to 5.1 μM. A few agents, such as the lactams 7 and 8, the camphanates 12a and 12b, the cyclohexanecarboxylates 19a and 19b, and, most notably, the (7S)-benzoate 15a, had negligible effects on polymerization, yielding IC50 values greater than 40μM. Ketone 9 showed strong inhibition of tubulin polymerization comparable to that of thiocolchicone (6). Optically active alcohol 11a and acyl esters 13a and 14a with a (7S)-configuration were more active than the (7R)-esters 13b and 14b. However, the esters 15a-17a with a (7S)-configuration were less active than the (7R)-isomers 15b-17b, in which the (7R)-benzoate 15b was at least 15-fold more inhibitory than the (7S)-isomer 15a. For the most part, the agents causing strongest inhibition of polymerization also caused the greatest inhibition of [3H]colchicine binding. NMR and optical rotatory data indicate that, in polar solvents, the equilibrium in esters with a 7-O-aroyl substituent, i.e., 15a,b, 16a,b, and 17a,b, is reversed from (aS) to (aR) or from (aR) to (aS), as compared to nonpolar solvents.

Notes: As a continuation of our previous studies on the synthesis and antiplatelet activity of quinolin-2(1H)-ones with an α-methylidene-γ-butyrolactone substituted at O(8), the O(6)- and N(1)-substituted isomers were synthesized and evaluated for antiplatelet activity against thrombin (Thr)-, arachidonic acid (AA)-, collagen (Col)-, and platelet-activating-factor (PAF)-induced aggregation in washed rabbit platelets. These compounds were synthesized from 6-hydroxyquinolin-2(1H)-one via alkylation and Reformatsky-type condensation (Schemes 1 and 2). All of them were found to inhibit the platelet aggregation perfectly which was induced by AA and Col. 6-Substituted isomers 5b-g exhibited very strong inhibitory activities against AA- and PAF- induced aggregation and are approximately ten times more potent than their 8-substituted counterparts. However, the 1-substituted (11a and 11b) and the 1,6-disubstituted (6) counterparts were relatively inactive. Their effects on the Ca2+-dependent vasoconstriction induced by high K+, and the phasic and tonic vasoconstrictions induced by norepinephrine (NE) in rat aorta were also evaluated. Except 5g, all of them were found to have significant inhibitory activity on the NE-induced phasic and tonic vasoconstrictions. Compounds 6 and 11b also exhibited strong inhibitory activity on high-K+ medium, Ca2+-induced vasoconstriction.

Notes: The photolysis of N-alkylpyridinium halides 9a-e in alkaline H2O gave 6-azabicyclo[3.1.0]hexenol derivatives 10a-e. N-Substituents bearing ether, acetal, and alcohol functions were found to do not adversely influence the photochemical reaction course. The free OH groups of the N-(3-hydroxypropyl) derivative 10d were protected by benzoylation. The ensuing dibenzoate 14 underwent stereocontrolled opening of the aziridine ring on reaction with MeSH/BF3 to give a thioether 15. With benzoic acid in CHCI3, 10d gave the 4-hydroxy-5-aminocyclopent-2-enyl benzoate 11. The meso-2-aminocyclopent-4-ene-1,3-diol 12 was obtained by hydrolysis of 11. On reaction with Boc2O and NaI, the aziridine ring of 14 was converted to a bicyclic compound 17. Hydrolysis of 17 provided the trans-1,3-diol 18, the epimer of 12. Face-selective dihydroxylation of Boc-protected 12 gave a meso-aminocyclopentanetetrol 23 which was characterized upon peracetylation. Dihydroxylation of 15 provided a racemic analogue of epi-mannostatin A (26).

Notes: An alternative synthesis of enantiomerically pure SDZ 220-881 (1a) and SDZ EAB 515 (1b) starting from L-Z-tyrosine is described.

Notes: Bicyclic thiohydantoins were synthesized in a stereoselective manner by reacting (2R)/(2S)-diastereoisomer mixtures of 1,3-thiazolidine-2,4-dicarboxylic acids or their dimethyl diesters with PhNCS. 5,5-Dimethyl-1,3-thiazolidine-2,4-dicarboxylic acid with PhNCS led to a cyclization involving the C=O group at the C(2) center of the thiazolidine ring, while the acid's dimethyl diester gave cyclization involving the C=O group at C(4). In contrast, reactions involving unsubstituted 1,3-thiazolidine-2,4-dicarboxylic acid or its dimethyl diester led to thiohydantoins in which the ring closure had taken place only with the COO group at C(4). Independently of the direction of the ring closure, all reactions produce exclusively products with the (R)-configuration at C(2). The configurational assignments were based on 1H- and 13C-NMR studies, and confirmed by X-ray crystallographic analyses.

Notes: The new, axially chiral bis(4,5-dihydrooxazoles) 4 have been synthesized in a straightforward manner, starting from the substituted, racemic 1,1′-biphenyl-2,2′-dicarboxylic acids 1 and optically active amino alcohols 2. The adducts were resolved by medium-performance liquid chromatography (MPLC; see Scheme 1). Formation of Cu1 complexes of 4 was followed by 1H-NMR spectroscopy. The catalytic behavior of these complexes has been investigated by asymmetric cyclopropanation of styrene with ethyl diazoacetate. Beside the influence of steric factors, a significant electronic effect on asymmetric induction could also be observed (see Scheme 2 and Table).

Notes: The synthesis of the enantiomerically pure, bridgehead-functionalized bicyclo[3.2.1]octanes 11 and 16, containing a conformationally fixed trihydroxypropyl (aminodihydroxypropyl) unit, as well as the X-ray structure of 11 are described. These compounds are of interest as sugar surrogates in the preparation of DNA analogs. Compounds 11 and 16 became available in 10 and 12 steps, respectively, and in an overall yield of 11 and 4% from D-arabinose via a highly stereoselective pinacol coupling as the key step.

Notes: New derivatives of campholenaldehyde (= 2-(2,2,3-trimethylcyclopent-3-enyl)ethanal bearing two cyclopropane moieties were synthesized, and the structure of the stereoisomer responsible for its exceptionally strong, diffusive, and natural sandalwood-oil scent, ((1S,2S)-1-methyl-2-{[1S,3R,5R)-1,2,2-trimethylbicyclo[3.1.0]hex-3-yl]methyl}cyclopropyl)methanol (13a), was elucidated.

Notes: Titanium-dioxide surfaces have been glycosylated with the benzyl-, 4-fluorobenzyl-, and acetyl-protected diazirines 1-3. The modified TiO2 surfaces were characterized by contact-angle measurement, X-ray photoelectron spectroscopy (XPES), and time-of-flight secondary-ion mass spectrometry (ToF-SIMS). The main by-products of the glucosidation (mostly azines and trehaloses) were identified. Their physisorption slightly reduces the efficiency of the glucosidation by 1 mM solution of 1 or 2 in CH2Cl2, but this influence is neutralized by repeating the glucosidation, or by using a 100 mM solution of the diazirines. The immobilized, acetylated glucosyl moieties were deacetylated in situ. Calculations based on the XPES peaks of Ti 2p and F 1s for the TiO2 surface modified with 2 indicated 1.5 ± 0.9 immobilized glucosyl moieties per nm2.

Notes: A Chemotaxonomic survey for biologically active compounds from Malaysian Calophyllum species led to the findings of the four new benzoylcoumarins 1a, 2, 3, and 4a (including the unusual prenylated 6-benzoylcoumann 1a), two uncommon coumarins 5 and 6a with a pyran-4-one moiety fused at C(6) and C(7), and compounds 7a, 9, and 10, all isolated from the bark of C. teysmannii var. inophylloide. Their structures were determined by spectroscopic analysis and chemical transformations. X-Ray crystal-structure determination of 2 provided information on the conformational preferences of substituents in this class of coumarins. The syntheses of the cytotoxic calanone (7a) and of some related coumarins are described.

Notes: The heme-thiolate protein chloroperoxidase (CPO) catalyzes the chlorination of activated C—H bonds. A reaction mechanism is proposed for this enzymatic transformation (Scheme 1), and a new iron(III) porphyrinate complex 13 is synthesized containing pentafluorophenyl groups at two meso-positions and a thiophenolato ligand coordinating to the Fe-atom (Schemes 2 and 3). Due to the presence of the electron-withdrawing substituents, the catalyst 13 is appreciably resistant to oxidants (HOCl) and chlorinates, e.g., monochlorodimedone (5), with turnover numbers up to 1530. The redox potential of 13, E0 = - 134 mV, and the Soret band (λmax 448 nm) of the CO adduct of the reduced state of 13 are close to the corresponding values of the enzyme CPO.

Notes: The chemical synthesis of 2′-amino-2′-deoxyribonucleosides of uracil, cytosine, adenine, and guanine, and their conversion into suitably protected 3′-phosphoramidite building blocks 35-40 for oligonucleotide synthesis are described. The aglycone and the 2′-amino functions were protected using the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group. The synthesis of the 3′-O-succinyl (3′-O-(3-carboxypropanoyl))-substituted starting nucleoside 41 is described and its behavior examined in solution and on solid phase with regard to an anticipated migration during 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) deprotection. Oligonucleotides were prepared using the new building blocks, and their hybridization properties were studied by UV-melting techniques.

Notes: Chiral supermolecules may be obtained from suitable achiral molecular constituents associated through a dissymmetrizing interaction mode. This is the case for the supermolecules I-IV formed by hydrogen-bonding association between the achiral complementary components 1a,b and 2a,b,c. The crystal structures of the supermolecular pairs I-III and of the homochiral aggregate of two ternary supermolecules IV have been determined. The structural data are discussed.

Notes: Various bifunctional amino-protecting groups such as the phthaloyl, succinyl, and glutaryl group were investigated as potential linker molecules for attachment to solid-support materials. Pentane-1,3,5-tricarboxylic acid 1,3-anhydride (16) offered the best properties and reacted with the amino groups of differently sugar-protected adenosine (see 20 and 22), cytidine (see 29), and guanosine derivatives (see 32) to the corresponding 2-(2-carboxyethyl)glutaryl derivatives 23, 24, 30, and 33. The usefulness of the new linker-type molecules was demonstrated by the solid-support synthesis of the potentially antivirally active 3′-deoxyadenylyl-(2′-5′)-2′-adenylic acid 2′-{2-[(adenin-9-yl)methoxy]ethyl} ester (38) starting from the 2′-end with N6,N6-[2-(2-carboxyethyl)glutaryl]-9-{{2-[(4,4′-dimethoxytrityl)ethoxy]methyl}adenine (12).

Notes: An efficient stereocontrolled synthesis of (S)-N-Cbz-serine (Cbz = benzyloxycarbonyl; 12) and of its (R)-enantiomer is reported. Kinetic resolution of the easily available racemic 3-(hydroxymethyl)-1,4-benzodiazepin-2-ones is performed in the key step via acetylation by the immobilized Mucor miehei lipase (Lipozyme IM) at 60°. This method is characterized by high enantiomer purity (ee's ges; 99%) of the intermediary alcohols (+)-8 and (+)-9 and acetates (-)-10 and (-)-11, as well as of the final products (S)- and (R)-N-Cbz-serine, simple recycling of the biocatalyst, complete recovery of 2-aminobenzophenones (3 and 4) and their recycling into production of 1,4-benzodiazepines, and possibility to selectively racemize ‘wrong’ enantiomers of the alcohols 8 and 9 in the presence of Amberlite CG 400.

Notes: The fate of an insect juvenile hormone analog applied to the insect body of the flesh fly (Sarcophaga bullata) or the tsetse fly (Glossina palpalis), respectively, was studied using three different radiolabeled positions in the parent biologically active compound 1. Several metabolites were found and analyzed. A mechanism of degradation of the applied molecule was designed using a combination of several radioanalytical methods. A unique monitoring of the applied compound and its metabolites was provided, based on the different radiolabeling of the structure (cf. 1a-1c), and established their fate in an insect body during a 10-day experiment. A 14C and 3H radiolabeling, respectively, was employed to synthesize three different radiolabeled forms 1a-1c derived from the parent non-labeled 1. A combination of three different ways of radiolabeling resulted in an advantage in tracing the metabolic pathway of degradation of the employed compound 1 in its radiolabeled forms 1a-1c.

Notes: Previous work has indicated orbital-symmetry effects upon forward electron transfer in bimolecular systems, with magnitude similar to that encountered in rigid monomolecular systems. The present work, which employs back electron transfer, supports and extends these earlier findings.

Notes: According to ab-initio calculations, the CF…HO H-bond in 1,3-diaxial 3-fluorocyclohexanol is characterized by d(F…H) = 2.08 Å, and ∠ (F…H—O) = 138°, and by ΔE between 1.2 and 4.1 kcal/mol, depending upon the reference system. Relative to the OH stretching frequency of axial cyclohexanol, the OH stretching frequency of 1,3-diaxial 3-fluorocyclohexanol is shifted by Δω = 7 cm-1. The rigid fluoro diols D-4 and L-4 were prepared from tetrahydroxy-p-benzoquinone in 11 steps and 1% overall yield. The IR spectrum of 4 in CCl4 soln. is characterized by Δν = 7 cm-1 for the axial and Δν = 44 cm-1 for the equatorial OH group. A relatively strong intramolecular CF…HO bond of 4 in CCl4 is evidenced by the large through-space coupling 5J(F,HO) of 9.3 Hz. Nevertheless, this FHO bond is disrupted in ethereal solvents, while the bifurcated O…HO bond subsists. In CCl4, the carbene generated from the glucosylidene-derived diazirine 5 reacted more rapidly with the axial OH group of D-4 and L-4 than with the equatorial one. This regioselectivity is in keeping with the weaker H-bond of the axial OH group. The regioselectivity is lower in ethers, but its solvent dependence does not parallel solvent basicity. This is not satisfactorily explained by the differential interaction of the ether solvents with the axial and equatorial OH groups, as evidenced by the solvent dependence of their chemical shift, but must also reflect the different interaction of the solvents with the carbene derived from 5, leading to ylides. The lower solvent dependence of the anomeric selectivity for the glycosidation of the equatorial OH group is a consequence of the coordination of the intermediate oxycarbenium ion with O—C(1) and O—C(3) rather than with the solvent. Under conditions of competitive glycosylation in CCl4, the fluoro alcohol D-22 reacted more slowly than the alcohol L-24, evidencing the intramolecular F…HO H-bond.