Design and synthesis of potent in vitro and in vivo anticancer agents based on 1-(3′,4′,5′-Trimethoxyphenyl)- 2-Aryl-1H-Imidazole

Romagnoli, Romeo, Baraldi, Pier Giovanni, Prencipe, Filippo, Oliva, Paola, Baraldi, Stefania, Tabrizi, Mojgan Aghazadeh, Lopez-Cara, Luisa Carlota, Ferla, Salvatore ORCID: https://orcid.org/0000-0002-5918-9237, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Hamel, Ernest, Ronca, Roberto, Bortolozzi, Roberta, Mariotto, Elena, Basso, Giuseppe and Viola, Giampietro 2016. Design and synthesis of potent in vitro and in vivo anticancer agents based on 1-(3′,4′,5′-Trimethoxyphenyl)- 2-Aryl-1H-Imidazole. Scientific Reports 6 , p. 26602. 10.1038/srep26602

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Abstract

A novel series of tubulin polymerization inhibitors, based on the 1-(3′,4′,5′-trimethoxyphenyl)-2-aryl-1H-imidazole scaffold and designed as cis-restricted combretastatin A-4 analogues, was synthesized with the goal of evaluating the effects of various patterns of substitution on the phenyl at the 2-position of the imidazole ring on biological activity. A chloro and ethoxy group at the meta- and para-positions, respectively, produced the most active compound in the series (4o), with IC50 values of 0.4-3.8 nM against a panel of seven cancer cell lines. Except in HL-60 cells, 4o had greater antiproliferative than CA-4, indicating that the 3′-chloro-4′-ethoxyphenyl moiety was a good surrogate for the CA-4 B-ring. Experiments carried out in a mouse syngenic model demonstrated high antitumor activity of 4o, which significantly reduced the tumor mass at a dose thirty times lower than that required for CA-4P, which was used as a reference compound. Altogether, our findings suggest that 4o is a promising anticancer drug candidate that warrants further preclinical evaluation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Publisher:	Nature Publishing Group
ISSN:	2045-2322
Date of First Compliant Deposit:	11 June 2016
Date of Acceptance:	3 May 2016
Last Modified:	05 Jan 2024 06:00
URI:	https://orca.cardiff.ac.uk/id/eprint/91753

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