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

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

doi:10.1080/14756366.2020.1838500

Rebeka Jójárt, István Zupkó + Show 6 more

Open Access

https://doi.org/10.1080/14756366.2020.1838500

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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.

Highlights

The development of anticancer agents is often based on synthetic modifications of endogenous compounds1
Drugs that interfere with tubulin polymerisation/depolymerisation dynamics might lead to suppression of the cell growth7–9
The synthesis of 3-N-benzyltriazolylmethyl-13a-oestrone derivatives substituted at C-2 or C-4 was started with the propargylation of 13a-oestrone 9 (Scheme 1)

Summary

Introduction

The development of anticancer agents is often based on synthetic modifications of endogenous compounds1 This approach might be limited by the retained original biological activity of the biomolecule. Combrestatin A-4 (CA-4) is a colchicine site-binding nanomolar antitubulin agent, arresting the cells in metaphase. It is assigned as a potent vascular disrupting agent. Replacement of methoxy groups with halogens and introduction of a triazole or tetrazole ring instead of an ethylene bridge might be a powerful strategy in the development of more effective antitubulin CA-4 derivatives (Figure 1). The triazole heterocycle is widely used in drug development according to its favourable characteristics It might enhance the stability against metabolic degradation and the Hbonding ability. This heterocyclic ring is an excellent mimetic of a peptide bond

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