SYNTHESIS AND STRUCTURE-ACTIVITY PROFILES OF A-HOMOESTRANES, THE ESTRATROPONES

2-Methoxyestradiol, a mammalian metabolite of estradiol, has reported antiangiogenic activity which has been proposed to be mediated through interaction at the colchicine binding site on the tubulin monomer. Su bsequent structure-activity studies of 2-methoxyestradiol have yielded highly potent steroidal inhibitors of tubulin polymerization. In an e ffort to probe the scope of binding at the colchicine binding site and the nature of the relationship between 2-methoxyestradiol and colchic ine, a series of colchicine/2-methoxyestradiol hybrids was synthesized . These A-homoestrane hybrid systems, collectively termed estratropone s, possessed an A-ring tropone system with the keto functionality at e ither the C-2, C-3, or C-4 position of the steroid nucleus. The estrat ropones were evaluated for their ability to inhibit the polymerization of tubulin using an in vitro purified bovine brain assay. Most of the se hybrids inhibit polymerization with greater potency than either of the natural products. The most potent of these congeners possessed an approximate 5-fold enhancement of the activity of colchicine for the i nhibition of tubulin polymerization. alpha-Substituents on the tropone ring showed varied effects on the activities for the two classes of e stratropones studied in this regard, the C-3 oxo and the C-4 oxo speci es. The 3-substituted 4-oxoestratropones exhibited antitubulin activit y according to Cl approximate to Br > OCH3, whereas the 4-substituted 3-oxoestratropones exhibited activity according to OCH3 > Br approxima te to Cl. It is unclear if these substituent factors are purely electr onic or steric effects or if the substituent operates indirectly by al tering the conformation of the nonplanar troponoid ring. The estratrop ones represent a new class of tubulin binding agents with potential an tiangiogenic utility.