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

Autor:	Manuel Medarde, M. González, María Ovejero-Sánchez, Rogelio González-Sarmiento, Alba Vicente-Blázquez, Rafael Peláez
Přispěvatelé:	Junta de Castilla y León, Instituto de Investigación Biomédica de Salamanca, Ministerio de Educación, Cultura y Deporte (España)
Jazyk:	angličtina
Rok vydání:	2021
Předmět:	RM1-950 01 natural sciences colchicine HeLa chemistry.chemical_compound sulphonamides Microtubule Tubulin Drug Discovery Sulphonamides Cytotoxic T cell Colchicine antimitotic Cytotoxicity Pharmacology biology 010405 organic chemistry General Medicine biology.organism_classification Molecular biology 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry tubulin Cell culture Docking (molecular) biology.protein structure–activity relationships Therapeutics. Pharmacology
Zdroj:	Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 1029-1047 (2021) GREDOS. Repositorio Institucional de la Universidad de Salamanca instname Digital.CSIC. Repositorio Institucional del CSIC
ISSN:	1475-6374 1475-6366
Popis:	© 2021 The Author(s). 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. M.G. acknowledges a predoctoral fellowship from the Junta de Castilla y León (ORDEN EDU/529/2017 de 26 de junio). M.O.-S. acknowledges a predoctoral fellowship from the IBSAL (IBpredoc17/00010). A.V.-B. acknowledges a predoctoral fellowship from the Spanish Ministerio de Educación, Cultura y Deporte (FPU15/02457).
Databáze:	OpenAIRE
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