Topics

Design and synthesis of fungal-selective resorcylate aminopyrazole Hsp90 inhibitors.

08:00 EDT 12th September 2019 | BioPortfolio

Summary of "Design and synthesis of fungal-selective resorcylate aminopyrazole Hsp90 inhibitors."

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 derivitization of resorcylate natural products to produce fungal-selective compounds, we have developed a series of synthetic aminopyrazole-substituted resorcylates with broad, potent, and fungal-selective Hsp90 inhibitory activity. Herein we describe the synthesis of this series, as well as the structure-activity relationships driving selectivity for Cryptococcus neoformans and Candida albicans, two pathogenic fungi of major clinical importance.

Affiliation

Journal Details

This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804
Pages:

Links

DeepDyve research library

PubMed Articles [16035 Associated PubMed Articles listed on BioPortfolio]

Recent Advances in the Discovery of Novel HSP90 Inhibitors: An Update from 2014.

HSP90 is a member in the family of heat shock proteins responsible for folding proteins into mature conformations and thus maintaining their biological function in cells. Since it is involved in all h...

Design, synthesis, and molecular docking studies of novel pyrazolyl 2-aminopyrimidine derivatives as HSP90 inhibitors.

A series of novel pyrazolyl 2-aminopyrimidine derivatives (7a-t) were designed based on scaffold hopping techniques, synthesized and biologically evaluated for their HSP90 inhibition and anticancer ac...

Traditional and Novel Mechanisms of Heat Shock Protein 90 (HSP90) Inhibition in Cancer Chemotherapy Including HSP90 Cleavage.

HSP90 is a molecular chaperone that increases the stability of client proteins. Cancer cells show higher HSP90 expression than normal cells because many client proteins play an important role in the g...

Structures of Hsp90α and Hsp90β bound to a purine-scaffold inhibitor reveal an exploitable residue for drug selectivity.

Hsp90α and Hsp90β are implicated in a number of cancers and neurodegenerative disorders but the lack of selective pharmacological probes confounds efforts to identify their individual roles. Here, w...

Design, synthesis and biological evaluation of trinary benzocoumarin-thiazoles-azomethines derivatives as effective and selective inhibitors of alkaline phosphatase.

Design, synthesis and characterization of new trinary Benzocoumarin-Thiazoles-Azomethine derivatives having three bioactive scaffolds in a single structural unit were carried out. The newly synthesize...

Clinical Trials [4061 Associated Clinical Trials listed on BioPortfolio]

A Study of HS-196, an HSP90 Inhibitor-linked NIR Probe for Solid Malignancies

HS-196 is near infrared red (NIR)-tethered HSP90 inhibitor for clinical imaging of selective tumor binding. HS-196 consists of a HSP90 inhibitor that binds competitively to the Hsp90 ATP b...

HS-201, an HSP90 Inhibitor-linked Verteporfin for Detection of Solid Malignancies

HS-201 is Verteporfin-tethered HSP90 inhibitor for clinical imaging of selective tumor binding. HS-201 consists of a HSP90 inhibitor that binds competitively to the Hsp90 ATP binding domai...

Safety and Activity of SNX-5422 Plus Ibrutinib in CLL

SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib re...

Efficacy and Safety of SNX-5422 Added to an Established Dose of Ibrutinib in CLL

SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib re...

Efficacy of Heat-shock Protein (HSP) Inhibitors in Myeloproliferative Syndromes (MPS)

Heat-shock proteins (HSP) have been very highly conserved throughout the evolution of species and are characterized by their chaperone function, thanks to their ability to prevent aggregat...

Medical and Biotech [MESH] Definitions

Compounds that bind to and inhibit enzymes involved in the synthesis of STEROIDS.

An approach, process, or methodology which emphasizes credible evidence and the best available scientific knowledge, judiciously integrated to achieve the best possible outcomes in structural design. For example, the design of a new OUTPATIENT CLINIC might incorporate a review of published research on outpatient clinic design, decisions on similar past projects, along with interviews with staff and consumers.

Compounds which inhibit the synthesis of proteins. They are usually ANTI-BACTERIAL AGENTS or toxins. Mechanism of the action of inhibition includes the interruption of peptide-chain elongation, the blocking the A site of ribosomes, the misreading of the genetic code or the prevention of the attachment of oligosaccharide side chains to glycoproteins.

A field of biological research combining engineering in the formulation, design, and building (synthesis) of novel biological structures, functions, and systems.

A class of MOLECULAR CHAPERONES whose members act in the mechanism of SIGNAL TRANSDUCTION by STEROID RECEPTORS.

Quick Search


DeepDyve research library

Relevant Topic

Pharmacy
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...


Searches Linking to this Article