New TRAP1 and Hsp90 chaperone inhibitors with cationic components: Preliminary studies on mitochondrial targeting

R Rondanin; G Lettini; P Oliva; R Baruchello; C Costantini; C Trapella; D Simoni; T Bernardi; L Sisinni; M Pietrafesa; G Ponterini; M P Costi; T Vignudelli; R Luciani; D S Matassa; F Esposito; M Landriscina

doi:10.1016/j.bmcl.2018.05.031

New TRAP1 and Hsp90 chaperone inhibitors with cationic components: Preliminary studies on mitochondrial targeting

Bioorg Med Chem Lett. 2018 Jul 15;28(13):2289-2293. doi: 10.1016/j.bmcl.2018.05.031. Epub 2018 May 15.

Authors

R Rondanin¹, G Lettini², P Oliva¹, R Baruchello¹, C Costantini¹, C Trapella¹, D Simoni¹, T Bernardi¹, L Sisinni², M Pietrafesa², G Ponterini³, M P Costi³, T Vignudelli³, R Luciani³, D S Matassa⁴, F Esposito⁵, M Landriscina⁶

Affiliations

¹ Dep. of Chemical and Pharmaceutical Sciences, University of Ferrara, Italy.
² Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
³ Dep. of Life Sciences, University of Modena and Reggio Emilia, Italy.
⁴ Dep. of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, Italy.
⁵ Dep. of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, Italy. Electronic address: franca.esposito@unina.it.
⁶ Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy; Dep. of Medical and Surgical Sciences, University of Foggia, Italy. Electronic address: matteo.landriscina@unifg.it.

PMID: 29807796
DOI: 10.1016/j.bmcl.2018.05.031

Abstract

TRAP1 (Hsp75) is the mitochondrial paralog of the Hsp90 molecular chaperone family. Due to structural similarity among Hsp90 chaperones, a potential strategy to induce apoptosis through mitochondrial TRAP1 ATPase inhibition has been envisaged and a series of compounds has been developed by binding the simple pharmacophoric core of known Hsp90 inhibitors with various appendages bearing a permanent cationic head, or a basic group highly ionizable at physiologic pH. Cationic appendages were selected as vehicles to deliver drugs to mitochondria. Indeed, masses of new derivatives were evidenced to accumulate in the mitochondrial fraction from colon carcinoma cells and a compound in the series, with a guanidine appendage, demonstrated good activity in inhibiting recombinant TRAP1 ATPase and cell growth and in inducing apoptotic cell death in colon carcinoma cells.

Keywords: Anticancer activity; Apoptosis; Lipophilic cations; Mitochondrial targeting; TRAP1 inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / antagonists & inhibitors
Apoptosis / drug effects
Cell Proliferation / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Guanidines / chemical synthesis
Guanidines / chemistry
Guanidines / pharmacology
HCT116 Cells
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Humans
Isoxazoles / chemical synthesis
Isoxazoles / chemistry
Isoxazoles / pharmacology*
Mitochondria / metabolism*
Molecular Structure
Onium Compounds / chemical synthesis
Onium Compounds / chemistry
Onium Compounds / pharmacology
Organophosphorus Compounds / chemical synthesis
Organophosphorus Compounds / chemistry
Organophosphorus Compounds / pharmacology
Pyridinium Compounds / chemical synthesis
Pyridinium Compounds / chemistry
Pyridinium Compounds / pharmacology

Substances

Enzyme Inhibitors
Guanidines
HSP90 Heat-Shock Proteins
Isoxazoles
Onium Compounds
Organophosphorus Compounds
Pyridinium Compounds
TRAP1 protein, human
Adenosine Triphosphatases