ISSN:
1434-1948
Keywords:
Antitumor drugs
;
Platinum
;
DNA
;
Dendrimers
;
L1210 Mouse leukemia
;
Chemistry
;
General Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
The synthesis and characterisation of the first generation of a poly(propyleneimine) dendrimer DAB(PA)4, substituted with four trans-diamminechloroplatinum moieties is reported. The compound DAB(PA-tPt-Cl)4 was designed to overcome two problems often associated with cisplatin resistance in cancer cells: (i) deactivation of the platinum species by intracellular thiolates and (ii) improved repair of crosslinks with DNA. The four-armed molecule can be expected to form crosslinks with DNA that are very different from the adducts formed by cisplatin. Also, the tetranuclear compound has four leaving groups, while cisplatin has only two. Therefore, DAB(PA-tPt-Cl)4 would be less susceptible towards inactivation by reaction with intracellular thiolates. A reaction with an excess of the model nucleobase guanosine 5′-monophosphate (GMP) confirmed that the tetranuclear compound is capable of binding a maximum of four nucleobases. Therefore, the inactivation of one or two arms would still leave the molecule with enough reactivity to form crosslinks with DNA. Cytotoxicity tests were performed on two mouse leukemia L1210 cell lines, both sensitive and resistant towards cisplatin, and in seven human tumor cell lines. In all cell lines, the tetranuclear compound showed a low cytotoxicity. It is suggested that the low activity is related to the structure of the compound. Probably the high charge (+6) at physiological pH and its branched structure hamper the molecule in crossing the cell membranes.
Additional Material:
1 Ill.
Type of Medium:
Electronic Resource
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