2. Academic Validation
  3. Synthesis and antiproliferative activity of 6BrCaQ-TPP conjugates for targeting the mitochondrial heat shock protein TRAP1

Synthesis and antiproliferative activity of 6BrCaQ-TPP conjugates for targeting the mitochondrial heat shock protein TRAP1

  • Eur J Med Chem. 2022 Feb 5;229:114052. doi: 10.1016/j.ejmech.2021.114052.
Clelia Mathieu 1,  Quentin Chamayou 2,  Thi Thanh Hyen Luong 2,  Delphine Naud 3,  Florence Mahuteau-Betzer 3,  Mouad Alami 2,  Elias Fattal 1,  Samir Messaoudi 2,  Juliette Vergnaud-Gauduchon 4
Affiliations

Affiliations

  • 1 Université Paris-Saclay, CNRS, Institut Galien-Paris Saclay, 92296, Châtenay-Malabry, France.
  • 2 Université Paris-Saclay, CNRS, BioCIS, 92290, Châtenay, Malabry, France.
  • 3 Institut Curie, Université PSL, CNRS UMR9187, Inserm U1196, Chemistry and Modeling for the Biology of Cancer, 91400, Orsay, France; Université Paris-Saclay, CNRS UMR9187, Inserm U1196, Chemistry and Modeling for the Biology of Cancer, 91400, Orsay, France.
  • 4 Université Paris-Saclay, CNRS, Institut Galien-Paris Saclay, 92296, Châtenay-Malabry, France. Electronic address: [email protected].
PMID: 34952432 DOI: 10.1016/j.ejmech.2021.114052
Abstract

A series of 6BrCaQ-Cn-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.

Keywords

6BrCaQ; Anti-Proliferative activity; HSP90; Mitochondrial targeting; TRAP1; Triphenylphosphonium TPP.

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