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EnglishA 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.
| Data di pubblicazione: | 2016 | |
| Titolo: | Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1-(3’,4’,5’-Trimethoxyphenyl)-2-Aryl-1H-Imidazole | |
| Autori: | Romagnoli, Romeo; Baraldi, Pier Giovanni; Prencipe, Filippo; Oliva, Paola; Baraldi, Stefania; Aghazadeh Tabrizi, Mojgan; Lopez Cara, Carlota; Ferla, Salvatore; Brancale, Andrea; Hamel, Ernest; Ronca, Roberto; Bortolozzi, Roberta; Mariotto, Elena; Basso, Giuseppe; Viola, Giampietro . | |
| Rivista: | SCIENTIFIC REPORTS | |
| Keywords: | Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cell Survival, Gene Expression Regulation, Neoplastic, HeLa CellsHL-60 CellsHT29 Cells, Humans, Jurkat CellsMCF-7 Cells, Mice, Models, Molecular, Molecular Structure, Neoplasms, Stilbenes, Tubulin Modulators, Xenograft Model Antitumor Assays | |
| Abstract in inglese: | 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. | |
| Digital Object Identifier (DOI): | 10.1038/srep26602 | |
| Handle: | http://hdl.handle.net/11392/2343844 | |
| Appare nelle tipologie: | 03.1 Articolo su rivista |
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