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.
Highlights
A novel series of tubulin polymerization inhibitors, based on the 1-(3′,4′,5′-trimethoxyphenyl)-2-aryl1H-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
Wang and co-workers reported the preparation of 1-(3′,4′,5′-trimethoxyphenyl)-2-(4′-N,N-dimethylaminophenyl)-1H-imidazole 3a, with antiproliferative activity inferior to that of CA-4 against HCT-15 and NCI-H460 cancer cell lines, with IC50 values of 80 and 270 nM, respectively[11]
The 1-(3′,4′,5′-trimethoxyphenyl)-2-aryl-1H imidazoles 4a–q were evaluated for their antiproliferative activity against a panel of seven human tumor cell lines and compared with the known 4′-methoxyphenyl and 2′-naphthyl imidazole analogues 3b and 3c, respectively, as well as CA-4 (1a) as reference compounds
Summary
Both HeLa and Jurkat cells treated with 4o (50, 100 and 250 nM) exhibited a remarkable increase in the percentage of cells with low Δψmt (Fig. 7, Panels A,C) This occurred in a time- and concentration-dependent fashion, and, in both cell lines, a significant increase was observed after a 6 h treatment. Both Mcl-1 and Bcl-2 undergo a dramatic decrease after a 24 h treatment at all compound concentrations examined, indicating that 4o induced downregulation of these proteins to disable their anti-apoptotic function. Even at the highest dose, 4o did not present any sign of toxicity and did not cause a decrease in animal body weight (data not shown)
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