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.

Highlights on Steroidal Arylidene Derivatives as a Source of Pharmacologically Active Compounds: A Review

“…In this context, over the years, a large number of bioactive heterocyclic steroidal derivatives have been synthesized, and some of them are already being clinically used [ 94 , 95 ]. Interestingly, diverse heterocyclic compounds, including arylpyrazolines and pyrazoles, arylpyrimidines, oxindoles, pyridones and pyridines as well as spiro-pyrrolidines were prepared from arylidenesteroids [ 4 , 18 , 42 , 49 , 53 , 56 , 76 , 93 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ].…”

“…Moreover, the reaction of these 16 E -arylideneandrostanes with phenylhydrazine hydrate in anhydrous MeOH under reflux during 12 h afforded the corresponding phenylpyrazolinyl substituted derivatives [ 97 ]. Furthermore, Naggar et al synthesized estrone- N -substituted pyrazolines from 16 E -arylidenoestrones by condensation with methylhydrazine or phenylhydrazine in refluxing dioxane for 5 h [ 99 ]. To stress that the information about the stereochemistry of 16,17-pyrazolinyl steroids is not always clear.…”

“…In fact, some authors indicated that C-C bound between C-16 and C-5′ is β [ 97 , 100 ]. On the other hand, the study reported by El-Naggar et al do not present any information about the stereochemistry of these compounds [ 99 ].…”