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.
CITATION STYLE
Das, S. K., Ghosh, A., Paul Chowdhuri, S., Halder, N., Rehman, I., Sengupta, S., … Das, B. B. (2018). Neutral Porphyrin Derivative Exerts Anticancer Activity by Targeting Cellular Topoisomerase i (Top1) and Promotes Apoptotic Cell Death without Stabilizing Top1-DNA Cleavage Complexes. Journal of Medicinal Chemistry, 61(3), 804–817. https://doi.org/10.1021/acs.jmedchem.7b01297
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