Synthesis and evaluation of anticancer activities of 2- or 4-substituted 3-(N-benzyltriazolylmethyl)-13α-oestrone derivatives

Rebeka Jójárt; Seyyed Ashkan Senobar Tahaei; Péter Trungel-Nagy; Zoltán Kele; Renáta Minorics; Gábor Paragi; István Zupkó; Erzsébet Mernyák

doi:10.1080/14756366.2020.1838500

Synthesis and evaluation of anticancer activities of 2- or 4-substituted 3-(N-benzyltriazolylmethyl)-13α-oestrone derivatives

J Enzyme Inhib Med Chem. 2021 Dec;36(1):58-67. doi: 10.1080/14756366.2020.1838500.

Authors

Rebeka Jójárt¹, Seyyed Ashkan Senobar Tahaei², Péter Trungel-Nagy¹, Zoltán Kele³, Renáta Minorics², Gábor Paragi⁴, István Zupkó², Erzsébet Mernyák¹

Affiliations

¹ Department of Organic Chemistry, University of Szeged, Szeged, Hungary.
² Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary.
³ Department of Medicinal Chemistry, University of Szeged, Szeged, Hungary.
⁴ MTA-SZTE Biomimetic Systems Research Group, University of Szeged, Szeged, Hungary.

Abstract

2- or 4-Substituted 3-N-benzyltriazolylmethyl-13α-oestrone derivatives were synthesised via bromination of ring A and subsequent microwave-assisted, Pd-catalysed C(sp²)-P couplings. The antiproliferative activities of the newly synthesised brominated and phosphonated compounds against a panel of human cancer cell lines (A2780, MCF-7, MDA-MB 231) were investigated by means of MTT assays. The most potent compound, the 3-N-benzyltriazolylmethyl-4-bromo-13α-oestrone derivative exerted substantial selective cell growth-inhibitory activity against A2780 cell line with a submicromolar IC₅₀ value. Computational calculations reveal strong interactions of the 4-bromo derivative with both colchicine and taxoid binding sites of tubulin. Disturbance of tubulin function has been confirmed by photometric polymerisation assay.

Keywords: Hirao reaction; antiproliferative effect; azide–alkyne cycloaddition; molecular dynamics; tubulin polymerisation.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Estrone / analogs & derivatives
Estrone / chemistry
Estrone / pharmacology*
Humans
Mice
Models, Molecular
Molecular Structure
NIH 3T3 Cells
Polymerization / drug effects
Structure-Activity Relationship
Tubulin / metabolism

Substances

Antineoplastic Agents
Tubulin
Estrone

Grants and funding

The work of Erzsébet Mernyák and Renáta Minorics in this project was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The work of Erzsébet Mernyák in this project was supported by the ÚNKP-19-4-SZTE-71, ‘NEW NATIONAL EXCELLENCE PROGRAM OF THE MINISTRY OF HUMAN CAPACITIES. This work was supported by National Research, Development and Innovation Office-NKFIH through project OTKA SNN 124329. Support from Ministry of Human Capacities [Grant 20391–296 3/2018/FEKUSTRAT] is acknowledged.