1. Synthesis and antiproliferative activity of 6BrCaQ-TPP conjugates for targeting the mitochondrial heat shock protein TRAP1.
- Author
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Mathieu C, Chamayou Q, Hyen Luong TT, Naud D, Mahuteau-Betzer F, Alami M, Fattal E, Messaoudi S, and Vergnaud-Gauduchon J
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, HSP90 Heat-Shock Proteins antagonists & inhibitors, HSP90 Heat-Shock Proteins chemistry, Humans, Membrane Potential, Mitochondrial drug effects, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, HSP90 Heat-Shock Proteins metabolism, Mitochondria metabolism, Organophosphorus Compounds chemistry, Quinolones chemistry
- Abstract
A series of 6BrCaQ-C
n -TPP conjugates 3a-f and 5 was designed and synthesized as a novel class of TRAP1 inhibitors. Compound 3a displayed an excellent anti-proliferative activity with mean GI50 values at a nanomolar level in a diverse set of human cancer cells (GI50 = 0.008-0.30 μM) including MDA-MB231, HT-29, HCT-116, K562, and PC-3 cancer cell lines. Moreover, the best lead compound 6BrCaQ-C10 -TPP induces a significant mitochondrial membrane disturbance combined to a regulation of HSP and partner protein levels as a first evidence that his mechanism of action involves the TRAP-1 mitochondrial Hsp90 machinery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)- Published
- 2022
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