ISSN:
1573-0646
Keywords:
gossypol
;
gossypolone
;
Schiffs base derivatives
;
breast cancer
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
,
Medicine
Notes:
Summary Preclinical and clinical studies have pointed to the antitumor potential of the naturally occurring polyphenolic binaphthyl dialdehyde, gossypol, as well as its purified (−,+) enantiomers. To explore further the antitumor properties of this multifunctional agent, we synthesized several reactive derivatives including the (−,+) enantiomers of gossypolone and four different gossypol Schiffs bases (AR1, AR2, AR3, AR4). The biological activities of these new agents were screened by measuring theirin vitro antiproliferative activity against malignant (MCF-7, MCF-7/adr) or immortalized (HBL-100) human breast epithelial cell lines. Racemic gossypolone showed relatively uniform antiproliferative activity against all of the breast epithelial cell lines with 3- to 5-fold less activity than (-)-gossypol against MCF-7 and MCF-7/adr cells. Of interest, the relative antitumor potency of purified gossypolone enantiomers was reverse that of gossypol enantiomers, since (+)-gossypolone showed up to 3-fold greater inhibition of MCF-7 culture growth than (-)-gossypolone. Of the Schiff's base derivatives only AR3 with its isopropyl amine substituent demonstrated cytotoxic activity comparable to that of (-)-gossypol; derivatives with ethyl, propyl, or butyl amine substituents (AR1, AR2, AR4) had little growth inhibitory activity at culture concentrations up to 25 μM. AR3 activity was greatest against HBL-100 and MCF-7 cells [MCF-7 IC50 values: AR3=0.9 μM, (-)-gossypol=2.3 μM]; unlike (-)-gossypol, however, AR3 showed substantially reduced activity against the multidrug-resistant subline, MCF-7/adr. These structure-activity comparisons suggest that isolation of (−,+)-enantiomers of AR3 and additional chemical modifications including the synthesis of an isopropyl amine Schiff's base of gossypolone will likely yield a newer generation of gossypol analogues with enhanced anticancer potential.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00873798
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