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Neutral PorphyrinnDerivative Exerts Anticancer Activitynby Targeting Cellular Topoisomerase I (Top1) and Promotes ApoptoticnCell Death without Stabilizing Top1-DNA Cleavage Complexes 中性卟啉衍生物通过靶向细胞拓扑异构酶I （Top1）发挥抗癌活性，并在不稳定Top1- dna切割复合物的情况下促进凋亡细胞死亡

Figshare Pub Date : 2018-01-26 DOI: 10.1021/acs.jmedchem.7b01297.s001

SubhenduK. Das (4754160), Arijit Ghosh (1304952), Srijita Paul Chowdhuri (4754163), Nyancy Halder (4754169), Ishita Rehman (4754166), Souvik Sengupta (192414), Krushna Chandra Sahoo (823974), Harapriya Rath (2414326), Benu Brata Das (14763)

{"title":"Neutral PorphyrinnDerivative Exerts Anticancer Activitynby Targeting Cellular Topoisomerase I (Top1) and Promotes ApoptoticnCell Death without Stabilizing Top1-DNA Cleavage Complexes","authors":"SubhenduK. Das (4754160), Arijit Ghosh (1304952), Srijita Paul Chowdhuri (4754163), Nyancy Halder (4754169), Ishita Rehman (4754166), Souvik Sengupta (192414), Krushna Chandra Sahoo (823974), Harapriya Rath (2414326), Benu Brata Das (14763)","doi":"10.1021/acs.jmedchem.7b01297.s001","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.7b01297.s001","url":null,"abstract":"Camptothecin (CPT) selectively trapsntopoisomerase 1-DNA cleavablencomplexes (Top1cc) to promote anticancer activity. Here, we reportnthe design and synthesis of a new class of neutral porphyrin derivativen5,10-bis(4-carboxyphenyl)-15, 20-bis(4-dimethylaminophenyl)porphyrinn(compound 8) as a potent catalytic inhibitor of humannTop1. In contrast to CPT, compound 8 reversibly bindsnwith the free enzyme and inhibits the formation of Top1cc and promotesnreversal of the preformed Top1cc with CPT. Compound 8 induced inhibition of Top1cc formation in live cells was substantiatednby fluorescence recovery after photobleaching (FRAP) assays. We establishednthat MCF7 cells treated with compound 8 trigger proteasome-mediatednTop1 degradation, accumulate higher levels of reactive oxygen speciesn(ROS), PARP1 cleavage, oxidative DNA fragmentation, and stimulatenapoptotic cell death without stabilizing apoptotic Top1-DNA cleavagencomplexes. Finally, compound 8 shows anticancer activitynby targeting cellular Top1 and preventing the enzyme from directlynparticipating in the apoptotic process.","PeriodicalId":522333,"journal":{"name":"Figshare","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147895437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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