ABSTRACT
We present the design, synthesis and biological activity of novel N-substituted benzimidazole based acrylonitriles as potential tubulin polymerization inhibitors. Their synthesis was achieved using classical linear organic and microwave assisted techniques, starting from aromatic aldehydes and N-substituted-2-cyanomethylbenzimidazoles. All newly prepared compounds were tested for their antiproliferative activity in vitro on eight human cancer cell lines and one reference non-cancerous assay. N,N-dimethylamino substituted acrylonitriles 30 and 41, bearing N-isobutyl and cyano substituents placed on the benzimidazole nuclei, showed strong and selective antiproliferative activity in the submicromolar range of inhibitory concentrations (IC50 0.2-0.6 µM), while being significantly less toxic than reference systems docetaxel and staurosporine, thus promoting them as lead compounds. Mechanism of action studies demonstrated that two most active compounds inhibited tubulin polymerization. Computational analysis confirmed the suitability of the employed benzimidazole-acrylonitrile skeleton for the binding within the colchicine binding site in tubulin, thus rationalizing the observed antitumor activities, and demonstrated that E-isomers are active substances. It also provided structural determinants affecting both the binding position and the matching affinities, identifying the attached NMe2 group as the most dominant in promoting the binding, which allows ligands to optimize favourable cationâââπ and hydrogen bonding interactions with Lys352.
Subject(s)
Acrylonitrile/pharmacology , Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Density Functional Theory , Tubulin/metabolism , Acrylonitrile/chemical synthesis , Acrylonitrile/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Polymerization/drug effects , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
The multistep synthesis of a series of substituted amidino-benzimidazolyl-furyl-phenyl-acrylic acid's esters and substituted amidino-benzimidazolyl-naphtho[2,1-b]furan-carboxylic acid's esters is described starting from corresponding 3-(2-furyl)-2-phenyl-acrylic acids. The new compounds were tested on the cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (HT 29), melanoma (HBL), and human fibroblasts cell line (WI38). All compounds inhibited the proliferation of tumor cell lines. Inhibitory effect of examined compounds depended on concentration, but without significant difference among the type of tumor cells. The compounds 2 and 5 exerted very low inhibitory effect on the growth of human fibroblasts. Unsubstituted derivative 8 has not inhibited any tested cell lines.
