title: Synthesis and antiproliferative evaluation of novel benzoimidazole-contained oxazole-bridged analogs of combretastatin A-4.
abstract: A series of novel oxazole-bridged analogs of combretastatin A-4 bearing a benzo[d]-imidazole as B ring were synthesized and evaluated for antiproliferative activities against five human cancer cell lines. Among all the synthesized compounds, the N-unsubstituted benzoimidazole analog 5 and the analogs 6b, 7a and 7b with a small hydrophobic group on nitrogen atom of benzoimidazole ring were identified as the most potent inhibitors of tumor cell growth with IC50 values at nanomolar levels (5, IC50=8.4 nM, HT29; 6b, 7a, 7b, IC50=9.6 nM, 3.8 nM, 3.0 nM, A549). In a murine H22 tumor xenograft model, compound 5 exhibited significant antitumor activity. The binding mode of compound 5 in the colchicine binding site of tubulin was probed.
authors: Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors: Jie
authors: J
authors: Zhou
authors: Jing
authors: J
authors: Jin
authors: Yi
authors: Y
authors: Zhang
authors: Yuwen
authors: Y
authors: Yin
authors: Xiaoguang
authors: X
authors: Chen
authors: Bailing
authors: B
authors: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry*; D001632:Bibenzyls / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001632:Bibenzyls; D010080:Oxazoles; C040105:combretastatin
keywords: Antiproliferative activity; Benzo[d]-imidazole; Combretastatin; Oxazole; Structure–activity relationship