Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1-(3 %26apos;,4 %26apos;,5 %26apos;-Trimethoxyphenyl)-2-Aryl-1H-Imidazole

作者：Romagnoli Romeo; Baraldi Pier Giovanni; Prencipe Filippo; Oliva Paola; Baraldi Stefania; Tabrizi Mojgan Aghazadeh; Carlota Lopez Cara Luisa; Ferla Salvatore; Brancale Andrea; Hamel Ernest; Ronca Roberto; Bortolozzi Roberta; Mariotto Elena; Basso Giuseppe; Viola Giampietro

来源：Scientific Reports, 2016, 6(1): 26602.

DOI：10.1038/srep26602

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.

• 出版日期2016-5-24
• 单位NIH