Synthesis and biological activity of 5-aryliden-2-thiohydantoin S-aryl derivatives

Alexander V Finko; Dmitry A Skvortsov; Dimitri N Laikov; Gleb M Averochkin; Egor A Dlin; Marina A Kalinina; Vladimir A Aladinskiy; Nataliya S Vorobyeva; Andrei V Mironov; Elena K Beloglazkina; Nikolay V Zyk; Yan A Ivanenkov; Alexander G Majouga

doi:10.1016/j.bioorg.2020.103900

Synthesis and biological activity of 5-aryliden-2-thiohydantoin S-aryl derivatives

Bioorg Chem. 2020 Jul:100:103900. doi: 10.1016/j.bioorg.2020.103900. Epub 2020 May 11.

Affiliations

¹ Department of Chemistry, Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russia. Electronic address: finko.alexander@gmail.com.
² Department of Chemistry, Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russia; Faculty of Biology and Biotechnologies, Higher School of Economics, Myasnitskaya 13, 101000 Moscow, Russia. Electronic address: skvorratd@mail.ru.
³ Department of Chemistry, Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russia.
⁴ Skolkovo Institute of Science and Technology, 4 Alfred Nobel Street, 143025 Skolkovo, Russia.
⁵ Laboratory of Medical Chemistry and Bioinformatics, Moscow Institute of Physics and Technology, Institutsky Pereulok 9, 141701 Dolgoprudny, Russia.
⁶ National Research Center «Kurchatov Institute», Akademika Kurchatova pl. 1, 123182 Moscow, Russia.
⁷ Department of Chemistry, Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russia; Laboratory of Medical Chemistry and Bioinformatics, Moscow Institute of Physics and Technology, Institutsky Pereulok 9, 141701 Dolgoprudny, Russia.
⁸ Department of Chemistry, Moscow State University, Leninskie Gory 1-3, 119991 Moscow, Russia; Skolkovo Institute of Science and Technology, 4 Alfred Nobel Street, 143025 Skolkovo, Russia; Chemistry Department. Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, 125047 Moscow, Russia.

PMID: 32428745
DOI: 10.1016/j.bioorg.2020.103900

Abstract

Three new and complementary approaches to S-arylation of 2-thiohydantoins have been developed: copper-catalyzed cross coupling with either arylboronic acids or aryl iodides under mild conditions, or direct nucleophilic substitution in activated aryl halides. For 38 diverse compounds, reaction yields for all three methods have been determined. Selected by molecular docking, they have been tested on androgen receptor activation, and p53-Mdm2 regulation, and A549, MCF7, VA13, HEK293T, PC3, LnCAP cell lines for cytotoxicity, Two of them turned out to be promising as androgen receptor activators (likely by allosteric regulation), and another one is shown to activate the p53 cascade. It is hoped that 2-thiohydantoin S-arylidenes are worth further studies as biologically active compounds.

Keywords: 2-Thiohydantoins; Androgen receptor; Aryliodides; Boronic acids; Chan−Evans−Lam reaction; Cross coupling; Cytotoxicity; In vitro; MDM2; Molecular docking; Nucleophilic substitution; Open flask; P53; S-arylation; Ullmann-type.

Publication types

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

MeSH terms

Allosteric Regulation / drug effects
Androgens / chemical synthesis
Androgens / chemistry*
Androgens / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects
Chemistry Techniques, Synthetic
HEK293 Cells
Humans
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / metabolism
Protein Interaction Maps / drug effects
Proto-Oncogene Proteins c-mdm2 / metabolism
Receptors, Androgen / metabolism
Thiohydantoins / chemical synthesis
Thiohydantoins / chemistry*
Thiohydantoins / pharmacology*
Tumor Suppressor Protein p53 / metabolism

Substances

Androgens
Antineoplastic Agents
Receptors, Androgen
Thiohydantoins
Tumor Suppressor Protein p53
Proto-Oncogene Proteins c-mdm2