Novel steroidal 1,3,4-thiadiazines: Synthesis and biological evaluation in androgen receptor-positive prostate cancer 22Rv1 cells.

Autor: Komendantova AS; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia., Scherbakov AM; Department of Experimental Tumor Biology, N.N. Blokhin National Medical Research Center of Oncology, 24 Kashirskoe Shosse, 115522 Moscow, Russia. Electronic address: alex.scherbakov@gmail.com., Komkov AV; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia., Chertkova VV; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia., Gudovanniy AO; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia., Chernoburova EI; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia., Sorokin DV; Department of Experimental Tumor Biology, N.N. Blokhin National Medical Research Center of Oncology, 24 Kashirskoe Shosse, 115522 Moscow, Russia., Dzichenka YU; Institute of Bioorganic Chemistry of NAS of Belarus, Laboratory of Protein Engineering, Academician V.F. Kuprevich Str. 5/2, Minsk, Belarus., Shirinian VZ; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia., Volkova YA; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia. Electronic address: yavolkova@gmail.com., Zavarzin IV; N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., 119991 Moscow, Russia.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2019 Oct; Vol. 91, pp. 103142. Date of Electronic Publication: 2019 Jul 23.
DOI: 10.1016/j.bioorg.2019.103142
Abstrakt: A flexible approach to previously unknown spirofused and linked 1,3,4-thiadiazine derivatives of steroids with selective control of heterocyclization patterns is disclosed. (N-Arylcarbamoyl)spiroandrostene-17,6' [1,3,4]thiadiazines and (N-arylcarbamoyl)17-[1',3',4']thiadiazine-substituted androstenes, novel types of heterosteroids, were prepared from 16β,17β-epoxypregnenolone and 21-bromopregna-5,16-dien-20-one in good to high yields by the treatment with oxamic acid thiohydrazides. The synthesized compounds were screened for antiproliferative activity against the human androgen receptor-positive prostate cancer cell line 22Rv1. Most of (N-arylcarbamoyl)17-[1',3',4']thiadiazine-substituted androstenes exhibit better antiproliferative potency (IC 50  = 2.1-6.6 µM) than the antiandrogen bicalutamide. Compounds 7d with IC 50  = 3.0 μM and 7j with IC 50  = 2.1 μM proved to be the most active in the series under study. Lead synthesized compound 7j downregulates AR expression and activity in 22Rv1 cells. NF-κB activity is also blocked in 7j-treated 22Rv1 cells. Apoptosis is considered as a possible mechanism of 7j-induced cell death.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: