Synthesis and biological evaluation of 4β-sulphonamido and 4β-[(4′-sulphonamido)benzamide]podophyllotoxins as DNA topoisomerase-IIα and apoptosis inducing agents

被引：17

作者：

Kamal, Ahmed ^{[1
]}

Suresh, Paidakula ^{[1
]}

Ramaiah, M. Janaki ^{[2
]}

Mallareddy, Adla ^{[1
]}

Imthiajali, Syed ^{[1
]}

Pushpavalli, S. N. C. V. L. ^{[2
]}

Lavanya, A. ^{[2
]}

Pal-Bhadra, Manika ^{[2
]}

机构：

[1] Indian Inst Chem Technol, Div Organ Chem, Hyderabad 500607, Andhra Pradesh, India

[2] Indian Inst Chem Technol, Ctr Chem Biol, Hyderabad 500607, Andhra Pradesh, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2012年 / 20卷 / 06期

关键词：

Etoposide; Cell cycle; Anticancer activity; Comet assay; Topo-II alpha enzyme; CELL-CYCLE ARREST; POTENTIAL ANTITUMOR AGENTS; PODOPHYLLOTOXIN DERIVATIVES; CARBONIC-ANHYDRASE; ONE-POT; ANTICANCER; INHIBITORS; EFFICIENT; KINASE; CYTOTOXICITY;

D O I：

10.1016/j.bmc.2012.01.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of new 4 beta-sulphonamido and 4 beta-[(4'-sulphonamido)benzamide] conjugates of podophyllotoxin (11a-j and 15a-g) were synthesized and evaluated for anticancer activity against six human cancer cell lines and found to be more potent than etoposide. Some of the compounds 11b, 11d and 11e that showed significant antiproliferative activity in Colo-205 cells, were superior to etoposide. The flow cytometric analysis indicates that these compounds (11b, 11d and 11e) showed G2/M cell cycle arrest and among them 11e is the most effective. It is observed that this compound (11e) caused both single-strand DNA breaks as observed by comet assay as well as double-strand DNA breaks as indicated by gamma-H2AX. Further 11e showed inhibition of topo-II alpha as observed from Western blot analysis and related studies. Compounds caused activation of ATM as well as Chk1 protein indicating that the compound caused effective DNA damage. Moreover activation of caspase-3, p21, p16, NF-kB and down regulation of Bcl-2 protein suggests that this compound (11e) has apoptotic cell death inducing ability, apart from acting as a topo-II alpha inhibitor. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：2054 / 2066

页数：13

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