Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons

被引：26

作者：

Beck, Daniel E. ^{[1
,2
]}

Lv, Wei ^{[1
,2
]}

Abdelmalak, Monica ^{[3
,4
]}

Plescia, Caroline B. ^{[3
,4
]}

Agama, Keli ^{[3
,4
]}

Marchand, Christophe ^{[3
,4
]}

Pommier, Yves ^{[3
,4
]}

Cushman, Mark ^{[1
,2
]}

机构：

[1] Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA

[2] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA

[3] NCI, Dev Therapeut Branch, Bethesda, MD 21892 USA

[4] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 21892 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2016年 / 24卷 / 07期

基金：

美国国家卫生研究院;

关键词：

Topoisomerase I; Indenoisoquinoline; Anticancer; Cytotoxicity; Tyrosyl DNA phosphodiesterase 1; Tyrosyl DNA phosphodiesterase 2; DNA PHOSPHODIESTERASE I; CLEAVAGE COMPLEXES; ANTICANCER AGENTS; NITRATED INDENOISOQUINOLINES; MJ-III-65; NSC-706744; INDIMITECAN LMP776; INDOTECAN LMP400; INHIBITORS; CAMPTOTHECIN; IDENTIFICATION;

D O I：

10.1016/j.bmc.2016.02.015

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：

Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds' activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogs were discovered through testing in human cancer cell cultures. A hydroxyethylaminopropyl side chain on the lactam nitrogen of two halogenated indenoisoquinoline Top1 inhibitors was found to also impart inhibitory activity against tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes that participate in the repair of DNA damage induced by Top1 poisons. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：1469 / 1479

页数：11

共 38 条

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[Anonymous], 2009, SYBYL X

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