Synthesis and Structure−Activity Profiles of A-Homoestranes, the Estratropones

• Published in: Journal of medicinal chemistry Vol. 40; no. 23; pp. 3836 - 3841
• Main Authors: Miller, Thomas A, Bulman, Amanda L, Thompson, Charles D, Garst, Michael E, Macdonald, Timothy L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 07-11-1997
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cattle; Colchicine - analogs & derivatives; Estradiol - analogs & derivatives; Estradiol - chemical synthesis; Estradiol - pharmacology; Estranes - chemical synthesis; Estranes - pharmacology; General aspects; Medical sciences; Neovascularization, Pathologic - drug therapy; Pharmacology. Drug treatments; Structure-Activity Relationship; Tubulin - metabolism; Antineoplastic agent; Steroid; Trienic compound; Polymerization; Ketone; In vitro; Estrane derivatives; Vascularization; Angiogenesis; Tubulin; Structure activity relation; Chemical homologation; Inhibitor; Neovascularization; Chemical synthesis; Antimitotic
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970323e

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. Subsequent structure−activity studies of 2-methoxyestradiol have yielded highly potent steroidal inhibitors of tubulin polymerization. In an effort to probe the scope of binding at the colchicine binding site and the nature of the relationship between 2-methoxyestradiol and colchicine, a series of colchicine/2-methoxyestradiol hybrids was synthesized. These A-homoestrane hybrid systems, collectively termed estratropones, possessed an A-ring tropone system with the keto functionality at either the C-2, C-3, or C-4 position of the steroid nucleus. The estratropones were evaluated for their ability to inhibit the polymerization of tubulin using an in vitro purified bovine brain assay. Most of these 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 inhibition of tubulin polymerization. α-Substituents on the tropone ring showed varied effects on the activities for the two classes of estratropones studied in this regard, the C-3 oxo and the C-4 oxo species. The 3-substituted 4-oxoestratropones exhibited antitubulin activity according to Cl ≈ Br > OCH3, whereas the 4-substituted 3-oxoestratropones exhibited activity according to OCH3 > Br ≈ Cl. It is unclear if these substituent factors are purely electronic or steric effects or if the substituent operates indirectly by altering the conformation of the nonplanar troponoid ring. The estratropones represent a new class of tubulin binding agents with potential antiangiogenic utility.