Journal article
Design and Synthesis of Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors
Journal of medicinal chemistry, Vol.63(5), pp.2139-2180
03/12/2020
DOI: 10.1021/acs.jmedchem.9b00826
PMCID: PMC7069776
PMID: 31513387
Abstract
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.
Details
- Title: Subtitle
- Design and Synthesis of Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors
- Creators
- David S. Huang - Boston UniversityEmmanuelle LeBlanc - University of TorontoTanvi Shekhar-Guturja - University of TorontoNicole Robbins - University of TorontoDamian J. Krysan - Roy J. and Lucille A. Carver College of MedicineJuan Pizarro - Tulane UniversityLuke Whitesell - University of TorontoLeah E. Cowen - University of TorontoLauren E. Brown - Boston University
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.63(5), pp.2139-2180
- DOI
- 10.1021/acs.jmedchem.9b00826
- PMID
- 31513387
- PMCID
- PMC7069776
- NLM abbreviation
- J Med Chem
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Publisher
- Amer Chemical Soc
- Number of pages
- 42
- Grant note
- R01AI120958 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Canada Research Chair in Microbial Genomics & Infectious Disease
- Language
- English
- Date published
- 03/12/2020
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984297432302771
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