New azole derivatives of [17(20)E]-21-norpregnene: Synthesis and inhibition of prostate carcinoma cell growth

Tatsiana S Dalidovich; Alaksiej L Hurski; Galina E Morozevich; Alexandra S Latysheva; Tatsiana A Sushko; Natallia V Strushkevich; Andrei A Gilep; Alexander Y Misharin; Vladimir N Zhabinskii; Vladimir A Khripach

doi:10.1016/j.steroids.2018.08.004

New azole derivatives of [17(20)E]-21-norpregnene: Synthesis and inhibition of prostate carcinoma cell growth

Steroids. 2019 Jul:147:10-18. doi: 10.1016/j.steroids.2018.08.004. Epub 2018 Aug 25.

Affiliations

¹ Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich str., 5/2, 220141 Minsk, Belarus.
² Orekhovich Institute of Biomedical Chemistry, Moscow, Russia.
³ Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich str., 5/2, 220141 Minsk, Belarus; Department of Bioengineering, School of Engineering, The University of Tokyo, Japan.
⁴ Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich str., 5/2, 220141 Minsk, Belarus. Electronic address: vz@iboch.by.

PMID: 30149075
DOI: 10.1016/j.steroids.2018.08.004

Abstract

A number of isoxazole, 1,2,3-triazole, tetrazole, and 1,2,4-oxadiazole derivatives of [17(20)E]-21-norpregnene comprising 3β-hydroxy-5-ene and 3-oxo-4-ene fragments were prepared. Among the key steps for the synthesis of isoxazoles, 1,2,3-triazoles, and tetrazoles were (i) 1,3-dipolar cycloaddition of nitrile oxides or azides to acetylenes or nitriles and ii) dehydration of 17β-hydroxy-17α-methylene-azoles to [17(20)E]-21-norpregnene derivatives. 1,2,4-Oxadiazoles were prepared through the formation of acetimidamides. Potency of the synthesized compounds to inhibit CYP17A1 and to suppress growth of prostate carcinoma cells was investigated. Among the new azole derivatives, four compounds were found possessing high anti-proliferative activity.

Keywords: Azoles; CYP17A1 inhibitors; LNCaP prostate carcinoma cells; PC-3 prostate carcinoma cells; [17(20)E]-21-Norpregnenes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Azoles / chemical synthesis
Azoles / chemistry
Azoles / pharmacology*
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Humans
Male
Molecular Structure
Norpregnadienes / chemical synthesis
Norpregnadienes / pharmacology*
Norpregnadienes / therapeutic use
PC-3 Cells
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / pathology
Tumor Cells, Cultured

Substances

(17(20)E)-21-norpregnene
Antineoplastic Agents
Azoles
Norpregnadienes