Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and their precursors as antileukemic agents

被引：58

作者：

Gowda, N. R. Thimme ^{[1
]}

Kavitha, C. V. ^{[2
]}

Chiruvella, Kishore K. ^{[2
]}

Joy, Omana ^{[2
]}

Rangappa, Kanchugarakoppal S. ^{[1
]}

Raghavan, Sathees C. ^{[2
]}

机构：

[1] Univ Mysore, Dept Studies Chem, Mysore 570006, Karnataka, India

[2] Indian Inst Sci, Dept Biochem, Bangalore 560012, Karnataka, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 16期

关键词：

Benzimidazole-5-carboxylic acid; Anticancer drugs; Chemotherapy; Cancer therapeutics; Apoptosis; DNA damage; VITRO ANTIPROLIFERATIVE ACTIVITY; CANCER-CELL LINES; IN-VIVO; BENZIMIDAZOLE DERIVATIVES; INHIBITORS; DNA; APOPTOSIS;

D O I：

10.1016/j.bmcl.2009.06.103

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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, H-1 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 IC50 value of 3 mu M. 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. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：4594 / 4600

页数：7

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