Design and synthesis of fungal-selective resorcylate aminopyrazole hsp90 inhibitors

Huang, David; Leblanc, Emmanuelle; Shekhar-Guturja, Tanvi; Robbins, Nicole; Krysan, Damian; Pizarro, Juan Carlos; Whitesell, Luke; Cowen, Leah E.; Brown, Lauren E.

Document type :

Article dans une revue scientifique: Article original

DOI :

10.1021/acs.jmedchem.9b00826

PMID :

31513387

Permalink :

http://hdl.handle.net/20.500.12210/74995

Title :

Design and synthesis of fungal-selective resorcylate aminopyrazole hsp90 inhibitors

Author(s) :

Huang, David [Auteur]
Leblanc, Emmanuelle [Auteur]
Shekhar-Guturja, Tanvi [Auteur]
Robbins, Nicole [Auteur]
Krysan, Damian [Auteur]
Pizarro, Juan Carlos [Auteur]
Whitesell, Luke [Auteur]
Cowen, Leah E. [Auteur]
Brown, Lauren E. [Auteur]

Journal title :

Journal of Medicinal Chemistry

Abbreviated title :

J. Med. Chem.

Publication date :

2019-09-12

ISSN :

1520-4804

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

The molecular chaperone Hsp90, essential in all eukaryotes, plays a multifaceted role in promoting survival, virulence, and drug resistance across diverse pathogenic fungal species. The chaperone is also critically important, ...
Show more >The molecular chaperone Hsp90, essential in all eukaryotes, plays a multifaceted role in promoting survival, virulence, and drug resistance across diverse pathogenic fungal species. The chaperone is also critically important, however, to the pathogen's human host, preventing the use of known clinical Hsp90 inhibitors in antifungal applications due to concomitant host toxicity issues. With the goal of developing Hsp90 inhibitors with acceptable therapeutic indices for the treatment of invasive fungal infections, we initiated a program to design and synthesize potent inhibitors with selective activity against fungal Hsp90 isoforms over their human counterparts. Building on our previously reported derivatization of resorcylate natural products to produce fungal-selective compounds, we have developed a series of synthetic aminopyrazole-substituted resorcylate amides with broad, potent, and fungal-selective Hsp90 inhibitory activity. Herein we describe the synthesis of this series, as well as biochemical structure-activity relationships driving selectivity for the Hsp90 isoforms expressed by Cryptococcus neoformans and Candida albicans, two pathogenic fungi of major clinical importance.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

INSERM
Université de Lille

Collections :

Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192

Submission date :

2022-06-15T13:57:46Z

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