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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, Brancale, Andrea, 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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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: 17 Mar 2021 02:45

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