Synthesis, molecular modeling and biological evaluation of potent analogs of 2-methoxyestradiol

Steroids
Nora Al-KazaaleTrond Vidar Hansen

Abstract

The endogenous steroid 2-methoxyestradiol (1) has attracted a great interest as a lead compound towards the development of new anti-cancer drugs. Herein, the synthesis, molecular modeling, anti-proliferative and anti-angiogenic effects of ten 2-ethyl and four 2-methoxy analogs of estradiol are reported. The ethyl group was introduced to the steroid A-ring using a novel Friedel-Crafts alkylation protocol. Several analogs displayed potent anti-proliferative activity with IC50-values in the submicromolar range towards the CEM human leukemia cancer cell line. As such, all of these compounds proved to be more active than the lead compound 2-methoxyestradiol (1) in these cells. The six most cytostatic analogs were also tested as anti-angiogenic agents using an in vitro tube formation assay. The IC50-values were determined to be in the range of 0.1 μM ± 0.03 and 1.1 μM ± 0.2. These six compounds were also modest inhibitors against tubulin polymerization with the most potent inhibitor was 14b (IC50 = 2.1 ± 0.1 μM). Binding studies using N,N'-ethylene-bis(iodoacetamide) revealed that neither14a or 14b binds to the colchicine binding site in the tubulin protein, in contrast to 2-methoxyestradiol (1). These observations were supported by ...Continue Reading

Citations

Jul 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Eirik J SolumTrond Vidar Hansen
Feb 11, 2021·Antioxidants·Paulina BastianMagdalena Gorska-Ponikowska

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