Potent Anti-Ovarian Cancer with Inhibitor Activities on Both Topoisomerase II and ^V600EBRAF of Synthesized Substituted Estrone Candidates

Abstract

A series of 16-(α-alkoxyalkane)-17-hydrazino-estra-1(10),2,4-trien[17,16-c]-3-ol (3a−l) and estra-1(10),2,4-trien-[17,16-c]pyrazoline-3-ol derivatives (4a−d) were synthesized from corresponding arylidines 2a,b which was prepared from estrone 1 as starting material. Condensation of 1 with aldehydes gave the corresponding arylidine derivatives 2a,b which were treated with hydrazine derivatives in alcohols to give the corresponding derivatives 3a−l, respectively. Additionally, treatment of 2a,b with methyl- or phenylhydrazine in ethanolic potassium hydroxide afforded the corresponding N-substituted pyrazoline derivatives 4a−d, respectively. All these derivatives showed potent anti-ovarian cancer both in vitro and in vivo. The mechanism of anti-ovarian cancer was suggested to process via topoisomerase II and V600EBRAF inhibition.

Keywords

• estrone derivatives
• hydrazine
• N-substituted pyrazoline
• anti-ovarian cancer
• topoisomerase II inhibitor
• kinase inhibitor