DEVELOPING GOSSYPOL DERIVATIVES WITH ENHANCED ANTITUMOR-ACTIVITY

Preclinical and clinical studies have pointed to the antitumor potenti al of the naturally occurring polyphenolic binaphthyl dialdehyde, goss ypol, as well as its purified (-,+) enantiomers. To explore further th e antitumor properties of this multifunctional agent, we synthesized s everal reactive derivatives including the (-,+) enantiomers of gossypo lone and four different gossypol Schiffs bases (AR1, AR2, AR3, AR4). T he biological activities of these new agents were screened by measurin g their in vitro antiproliferative activity against malignant (MCF-7, MCF-7/adr) or immortalized (HBL-100) human breast epithelial cell line s. Racemic gossypolone showed relatively uniform antiproliferative act ivity against all of the breast epithelial cell lines with 3- to 5-fol d less activity than (-)-gossypol against MCF-7 and MCF-7/adr cells. O f interest, the relative antitumor potency of purified gossypolone ena ntiomers was reverse that of gossypol enantiomers, since (+)-gossypolo ne showed up to 3-fold greater inhibition of MCF-7 culture growth than (-)-gossypolone. Of the Schiff's base derivatives only AR3 with its i sopropyl 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 mu M. AR3 activity was greatest again st HBL-100 and MCF-7 cells [MCF-7 IC50 values: AR3 = 0.9 mu M, (-)-gos sypol = 2.3 mu M]; unlike (-)-gossypol, however, AR3 showed substantia lly reduced activity against the multidrug-resistant subline, MCF-7/ad r. These structure-activity comparisons suggest that isolation of (-,)-enantiomers of AR3 and additional chemical modifications including t he synthesis of an isopropyl amine Schiffs base of gossypolone will li kely yield a newer generation of gossypol analogues with enhanced anti cancer potential.