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 López Cara, Luisa Carlota We acknowledge “Proyecto de Excelencia de la Consejeria de Innovacion y Ciencia de la Junta de Andalucia, Spain ref. P12-CTS-696” for its financial support. We also acknowledge the support of the Life Science Research Net- work Wales grant no. NRNPGSep14008, an initiative funded through the Welsh Government’s Ser Cymru program. 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. 2024-04-30T09:18:35Z 2024-04-30T09:18:35Z 2016-05-24 journal article Romagnoli, R., Baraldi, P., Prencipe, F. et al. Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1-(3′,4′,5′-Trimethoxyphenyl)-2-Aryl-1H-Imidazole. Sci Rep 6, 26602 (2016). https://doi.org/10.1038/srep26602 https://hdl.handle.net/10481/91275 10.1038/srep26602 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Springer Nature