Neutral Porphyrin Derivative Exerts Anticancer Activity by Targeting Cellular Topoisomerase I (Top1) and Promotes Apoptotic Cell Death without Stabilizing Top1-DNA Cleavage Complexes

被引：26

作者：

Das, Subhendu K. ^{[1
]}

Ghosh, Arijit ^{[1
]}

Chowdhuri, Srijita Paul ^{[1
]}

Halder, Nyancy ^{[2
]}

Rehman, Ishita ^{[1
]}

Sengupta, Souvik ^{[1
,3
]}

Sahoo, Krushna Chandra ^{[2
]}

Rath, Harapriya ^{[2
]}

Das, Benu Brata ^{[1
]}

机构：

[1] Indian Assoc Cultivat Sci, Dept Biol Chem, Lab Mol Biol, 2A & 2B,Raja SC Mullick Rd, Kolkata 700032, India

[2] Indian Assoc Cultivat Sci, Dept Inorgan Chem, 2A & 2B,Raja SC Mullick Rd, Kolkata 700032, India

[3] Ahmedabad Univ, Sch Arts & Sci, Div Biol & Life Sci, Cent Campus, Ahmadabad 380009, Gujarat, India

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 03期

基金：

英国惠康基金;

关键词：

DNA TOPOISOMERASE; LEISHMANIA-DONOVANI; MESO-TETRAPHENYLPORPHIN; SPINOCEREBELLAR ATAXIA; SUBSTITUTED PORPHYRINS; BIOLOGICAL EVALUATION; ELECTRON-TRANSFER; INHIBITORS; CAMPTOTHECIN; TDP1;

D O I：

10.1021/acs.jmedchem.7b01297

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Camptothecin (CPT) selectively traps topoisomerase 1-DNA cleavable complexes (Top1cc) to promote anticancer activity. Here, we report the design and synthesis of a new class of neutral porphyrin derivative 5,10-bis(4-carboxyphenyl)-15, 20-bis(4-dimethylaminophenyl)porphyrin (compound 8) as a potent catalytic inhibitor of human Top1. In contrast to CPT, compound 8 reversibly binds with the free enzyme and inhibits the formation of Top1cc and promotes reversal of the preformed Top1cc with CPT. Compound 8 induced inhibition of Top1cc formation in live cells was substantiated by fluorescence recovery after photobleaching (FRAP) assays. We established that MCF7 cells treated with compound 8 trigger proteasome-mediated Top1 degradation, accumulate higher levels of reactive oxygen species (ROS), PARP1 cleavage, oxidative DNA fragmentation, and stimulate apoptotic cell death without stabilizing apoptotic Top1-DNA cleavage complexes. Finally, compound 8 shows anticancer activity by targeting cellular Top1 and preventing the enzyme from directly participating in the apoptotic process.

引用

页码：804 / 817

页数：14