title: Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and their precursors as antileukemic agents.
abstract: We report here the synthesis and preliminary evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives 6(a-k) and their precursors 5(a-k) as potential chemotherapeutic agents. In each case, the structures of the compounds were determined by FTIR, (1)H NMR and mass spectroscopy. Among the synthesized molecules, methyl 1-(4-methoxyphenethyl)-2-(4-fluoro-3-nitrophenyl)-1H-benzimidazole-5-carboxylate (5a) induced maximum cell death in leukemic cells with an IC(50) value of 3 microM. Using FACS analysis we show that the compound 5a induces S/G2 cell cycle arrest, which was further supported by the observed down regulation of CDK2, Cyclin B1 and PCNA. The observed downregulation of proapoptotic proteins, upregulation of antiapoptotic proteins, cleavage of PARP and elevated levels of DNA strand breaks indicated the activation of apoptosis by 5a. These results suggest that 5a could be a potent anti-leukemic agent.
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Mysore 570 006, India.
authors.forename: N R Thimme
authors.initials: NR
authors.lastname: Gowda
authors.forename: C V
authors.initials: CV
authors.lastname: Kavitha
authors.forename: Kishore K
authors.initials: KK
authors.lastname: Chiruvella
authors.forename: Omana
authors.initials: O
authors.lastname: Joy
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
authors.forename: Sathees C
authors.initials: SC
authors.lastname: Raghavan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C534699:CCNB1 protein, human; D002264:Carboxylic Acids; D019926:Cyclin B; D056744:Cyclin B1; D018809:Proliferating Cell Nuclear Antigen; D051357:Cyclin-Dependent Kinase 2