Methoxy and bromo scans on N-(5-methoxyphenyl) methoxybenzenesulphonamides reveal potent cytotoxic compounds, especially against the human breast adenocarcinoma MCF7 cell line

Myriam González,María Ovejero-Sánchez,Alba Vicente-Blázquez,Manuel Medarde,Rogelio González-Sarmiento,Rafael Peláez

doi:10.1080/14756366.2021.1925265

Abstract

Thirty seven N-(5-methoxyphenyl)-4-methoxybenzenesulphonamide with methoxy or/and bromo substitutions (series 1-4) and with different substituents on the sulphonamide nitrogen have been synthesised. 21 showed sub-micromolar cytotoxicity against HeLa and HT-29 human tumour cell lines, and were particularly effective against MCF7. The most potent series has 2,5-dimethoxyanilines, especially the 4-brominated compounds 23–25. The active compounds inhibit microtubular protein polymerisation at micromolar concentrations, thus pointing at tubulin as the target. Co-treatment with the MDR inhibitor verapamil suggests that they are not MDR substrates. Compound 25 showed nanomolar antiproliferative potency. It severely disrupts the microtubule network in cells and arrests cells at the G2/M cell-cycle phase, thus confirming tubulin targeting. 25 triggered apoptotic cell death, and induced autophagy. Docking studies suggest binding in a distinct way to the colchicine site. These compounds are promising new antitumor agents acting on tubulin.

Highlights

Microtubule dynamics is a very well-established target in antitumor, antiparasitic, herbicidal, and antifungal chemotherapy[1,2].Many microtubule-targeting drugs act by binding to tubulin, with some of them causing microtubule destabilisation (MDA, such as colchicine or vincristine), and others stabilisation (MSA, such as the taxanes) through binding to several binding sites[3]
In an attempt to find new antimitotic sulphonamides with TMP replacements we have explored the effect of additional methoxy and/or bromo substituents at different positions on the basic pharmacophore of the TMP moiety: a phenyl ring with a 5-methoxy aimed at recognising the thiol group of Cys241b of tubulin
A focussed library of 37 new sulphonamides that represents a scan of the substitution of hydrogen atoms on the anilide ring of the basic colchicine-binding site pharmacophore N-(5-methoxyphenyl)-4-methoxybenzenesulphonamides with methoxy and/or bromo groups, grouped in 4 structural series, has been successfully prepared

Summary

Introduction

Many microtubule-targeting drugs act by binding to tubulin, with some of them causing microtubule destabilisation (MDA, such as colchicine or vincristine), and others stabilisation (MSA, such as the taxanes) through binding to several binding sites[3]. Several colchicine-site ligands have reached clinical use as antiparasitic and antitumor drugs, such as the benzimidazoles nocodazole and albendazole[6], the stilbene combretastatin A-4 (CA-4)[7], or the sulphonamides ABT-751 or T1380673. Each class of colchicine site drugs has liabilities, such as the low aqueous solubility and the instability of combretastatins[7], the insufficient potency of ABT-7513, or the development of resistance by cancer cells[8], which urge for new medicinal chemistry efforts. Diarylsulphonamides are privileged scaffolds in medicinal chemistry and well-known anticancer agents[3], with benzenesulphonamides carrying 3,4,5-trimethoxyphenyl (TMP) rings acting as tubulin inhibitors, such as N-(3,4,5-trimethoxyphenyl)-4-

Methods

Results

Conclusion