title: Synthesis and cytotoxic activity of novel tetrahydrobenzodifuran-imidazolium salt derivatives.
abstract: The synthesis of a series of novel 4-substituted 2,3,6,7-tetrahydrobenzo [1,2-b;4,5-b']difuran-1H-imidazolium salts is presented. The biological properties of the compounds were evaluated in vitro against a panel of human tumor cell lines. Results suggest that the 5,6-dimethyl-benzimidazole or 2-methyl-benzimidazole ring, and substitution of the imidazolyl-3-position with a 2-naphthylmethyl substituent or 2-naphthylacyl substituent, were important to the cytotoxic activity. Notably, 3-(2-Naphthylmethyl)-1-((2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b']difuran-4-yl)methyl)-1H-5,6-dimethyl-benzimidazol-3-ium bromide (42) was found to be the most potent derivative against five human tumor cell lines with IC50values of 1.06-4.34μM and more selective towards SMMC-7721, A549 and SW480 cell lines. 3-(2-Naphthylacyl)-1-((2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b']difuran-4-yl)methyl)-1H-2-methyl-benzimidazol-3-ium bromide (37) showed higher selectivity to SMMC-7721 and MCF-7 cell lines with IC50values 2.7-fold and 8.4-fold lower than DDP. Study regarding to the antitumor mechanism of action showed that compound 37 could induce cell cycle G1 phase arrest and apoptosis in SMMC-7721 cells.
authors.affiliation: Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650091, PR China.
authors.forename: Chao-Bo
authors.initials: CB
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650091, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650091, PR China.
authors.forename: Zheng-Fen
authors.initials: ZF
authors.lastname: Liu
authors.affiliation: Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650091, PR China.
authors.forename: Sheng-Zu
authors.initials: SZ
authors.lastname: Duan
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, United States.
authors.forename: Min-Yan
authors.initials: MY
authors.lastname: Li
authors.affiliation: Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650091, PR China. Electronic address: chenwenchem@163.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Science, Kunming 650204, PR China. Electronic address: liyanb@mail.kib.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650091, PR China.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650091, PR China. Electronic address: xdyang@ynu.edu.cn.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001572:Benzofurans; D007093:Imidazoles; C109865:2-methylbenzimidazole
keywords: Apoptosis; Cell cycle; Cytotoxic activity; Imidazolium salts; Tetrahydrobenzodifurans