US EPA

7463378 

Journal Article 

Synthesis and anticancer activity of novel water soluble benzimidazole carbamates 

Cheong, JE; Zaffagni, M; Chung, I; Xu, Y; Wang, Y; Jernigan, FE; Zetter, BR; Sun, L 

2018 

Yes 

European Journal of Medicinal Chemistry
ISSN: 0223-5234
EISSN: 1768-3254 

Elsevier Masson SAS 

144 

372-385 

English 

10.1016/j.ejmech.2017.11.037 

Metastases account for more than 90% of all cancer deaths and respond poorly to most therapies. There remains an urgent need for new therapeutic modalities for the treatment of advanced metastatic cancers. The benzimidazole methylcarbamate drugs, commonly used as anti-helmitics, have been suggested to have anticancer activity, but progress has been stalled by their poor water solubility and poor suitability for systemic delivery to disseminated cancers. We synthesized and characterized the anticancer activity of novel benzimidazoles containing an oxetane or an amine group to enhance solubility. Among them, the novel oxetanyl substituted compound 18 demonstrated significant cytotoxicity toward a variety of cancer cell types including prostate, lung, and ovarian cancers with strong activity toward highly aggressive cancer lines (IC50: 0.9–3.8 μM). Compound 18 achieved aqueous solubility of 361 μM. In a mouse xenograft model of a highly metastatic human prostate cancer, compound 18 (30 mg/kg) significantly inhibited the growth of established tumors (T/C: 0.36) without noticeable toxicity. © 2017 Elsevier Masson SAS 

Anticancer activity; Benzimidazole; Oxetane; Solubility; (3 methyloxetan 3 yl)methyl [5 (propylthio) 1h benzo[d]imidazol 2 yl]carbamate; 2 (dimethylamino)ethyl (5 benzoyl 1h benzo[d]imidazol 2 yl)carbamate; 2 (dimethylamino)ethyl [5 (4 fluorobenzoyl) 1h benzo[d]imidazol 2 yl]carbamate; 2 (dimethylamino)ethyl [5 (phenylthio) 1h benzo[d]imidazol 2 yl]carbamate; 2 (dimethylamino)ethyl [5 (propylthio) 1h benzo[d]imidazol 2 yl]carbamate; 3 (dimethylamino)propyl [5 (4 fluorobenzoyl) 1h benzo[d]imidazol 2 yl]carbamate; 3 (dimethylamino)propyl [5 (propylthio) 1h benzo[d]imidazol 2 yl]carbamate; antineoplastic agent; benzimidazole derivative; carbamic acid derivative; mebendazole; methyl [5 [2 [methyl(oxetan 3 yl)amino]benzoyl] 1h benzo[d]imidazol 2 yl]carbamate; methyl [5 [3 (4 methylpiperazin 1 yl)phenoxy] 1h benzo[d]imidazol 2 yl]carbamate; methyl [5 [[6 (4 methylpiperazin 1 yl)pyridin 2 yl]oxy] 1h benzo[d]imidazol 2 yl]carbamate; oxetan 3 yl (5 benzoyl 1h benzo[d]imidazol 2 yl)carbamate; oxetan 3 yl [5 (phenylthio) 1h benzo[d]imidazol 2 yl) carbamate; oxetan 3 yl [5 (propylthio) 1h benzo[d]imidazol 2 yl)carbamate; paclitaxel; unclassified drug; [5 [4 [methyl(oxetan 3 yl) amino]benzoyl] 1h benzo[d]imidazol 2 yl]carbamate; antineoplastic agent; benzimidazole derivative; carbamic acid derivative; water; A-549 cell line; animal experiment; animal model; antineoplastic activity; Article; Calu-1 cell line; cancer inhibition; cell viability; controlled study; crystal structure; drug cytotoxicity; drug design; drug efficacy; drug solubility; drug synthesis; EC50; female; human; human cell; in vitro study; in vivo study; male; molecular docking; mouse; NCI-H157 cell line; nonhuman; PC-3M cell line; SK-OV-3 cell line; structure activity relation; tumor xenograft; animal; cell proliferation; cell survival; chemical structure; chemistry; dose response; drug effects; experimental neoplasm; pathology; solubility; synthesis; tumor cell culture; Animals; Antineoplastic Agents; Benzimidazoles; Carbamates; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Humans; Male; Mice; Molecular Docking Simulation; Molecular Structure; Neoplasms, Experimental; Solubility; Structure-Activity Relationship; Tumor Cells, Cultured; Water