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An A-ring substituted evodiamine derivative with potent anticancer activity against human non-small cell lung cancer cells by targeting heat shock protein 70

Cited 1 time in Web of Science Cited 1 time in Scopus
Authors

Min, Hye-Young; Lim, Yijae; Kwon, Hyukjin; Boo, Hye-Jin; Yeob Hyun, Seung; Hong, Junhwa; Hong, Suckchang; Lee, Ho-Young

Issue Date
2023-05
Publisher
Elsevier BV
Citation
Biochemical Pharmacology, Vol.211, p. 115507
Abstract
The heat shock protein (HSP) system is essential for the conformational stability and function of several proteins. Therefore, the development of efficacious HSP-targeting anticancer agents with minimal toxicity is required. We previously demonstrated that evodiamine is an anticancer agent that targets HSP70 in non-small cell lung cancer (NSCLC) cells. In this study, we synthesized a series of evodiamine derivatives with improved efficacy and limited toxicity. Among the 14 evodiamine derivatives, EV408 (10-hydroxy-14-methyl-8,13,13b,14-tetrahydroindolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5(7H)-one) exhibited the most potent inhibitory effects on viability and colony formation under anchorage-dependent and -independent culture conditions in various human NSCLC cells, including those that are chemoresistant, by inducing apoptosis. In addition, EV408 suppressed the cancer stem-like cell (CSC) population of NSCLC cells and the expression of stemness-associated markers. Mechanistically, EV408 inhibited HSP70 function by directly binding and destabilizing the HSP70 protein. Furthermore, EV408 significantly inhibited the growth of NSCLC cell line tumor xenografts without overt toxicity. Additionally, EV408 had a negligible effect on the viability of normal cells. These results suggest the potential of EV408 as an efficacious HSP70-targeting evodiamine derivative with limited toxicity that inhibits both non-CSC and CSC populations in NSCLC.
ISSN
0006-2952
URI
https://hdl.handle.net/10371/201985
DOI
https://doi.org/10.1016/j.bcp.2023.115507
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  • College of Pharmacy
  • Department of Manufacturing Pharmacy
Research Area Development of methodologies using metal catalyst, Total synthesis of natural products

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