Switching Residues: A Platform for the Synthesis of Fidaxomicin Antibiotics DOI Creative Commons
Erik Jung, Tizian Griesser, Jordan Costafrolaz

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 64(7)

Published: Nov. 25, 2024

Peripheral modification is often the main approach to optimize natural products for improved biological activity or desired physicochemical properties. This procedure inevitably increases molecular weight, accompanied by undesired increased lipophilicity. Removing structural elements from not always tolerated. also case antibiotic fidaxomicin (Fdx), where every component has been shown be crucial activity. In this work, we demonstrate how residue switching can maintain of Fdx derivatives replacing rhamnoside-dichlorohomoorsellinate moiety with smaller, more polar building blocks. We used palladium-catalysed allylic substitution selectively install N-nucleophiles on core Fdx. The new were designed mimic binding bacterial RNA polymerase. Evaluation against Mycobacterium tuberculosis, Clostridioides difficile, and Gram-negative model organism Caulobacter crescentus demonstrated that newly introduced residues restore activity, which was further supported on-target polymerase assays. combined an organocatalysed novioside acylation protocol enable functionalisation two vectors in one pot. platform greatly expands accessible chemical space enables future development systemic antibiotics.

Language: Английский

Move over COVID, Tuberculosis Is Once again the Leading Cause of Death from a Single Infectious Disease DOI
Tomayo Berida, Craig W. Lindsley

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(24), P. 21633 - 21640

Published: Dec. 9, 2024

Language: Английский

Citations

3
Exploring the Chemistry and Applications of Thio-, Seleno-, and Tellurosugars DOI Creative Commons
Roxana Martínez-Pascual, M. Valera‐Zaragoza, José G. Fernández‐Bolaños

et al.

Molecules, Journal Year: 2025, Volume and Issue: 30(9), P. 2053 - 2053

Published: May 5, 2025

Given the crucial roles of carbohydrates in energy supply, biochemical processes, signaling events and pathogenesis several diseases, development carbohydrate analogues, called glycomimetics, is a key research area Glycobiology, Pharmacology, Medicinal Chemistry. Among many structural transformations explored, replacement endo- exocyclic oxygen atoms by carbon (carbasugars) or heteroatoms, such as nitrogen (aza- iminosugars), phosphorous (phosphasugars), sulfur (thiosugars), selenium (selenosugars) tellurium (tellurosugars) have garnered significant attention. These isosteric substitutions can modulate bioavailability, stability, bioactivity, while introducing new properties, redox activity, interactions with pathological lectins enzymes, cytotoxic effects. In this manuscript we focused on three major families glycomimetics: thio-, seleno-, tellurosugars. We provide comprehensive review most relevant synthetic pathways leading to primarily at endocyclic glycosidic positions. The scope includes metal-catalyzed reactions, organocatalysis, electro- photochemical transformations, free-radical automated syntheses. Additionally, mechanistic insights, stereoselectivity, biological properties are also discussed. diversity promising bioactivities these glycomimetics underscore their significance area.

Language: Английский

Citations

0
Switching Residues: A Platform for the Synthesis of Fidaxomicin Antibiotics DOI Creative Commons
Erik Jung, Tizian Griesser, Jordan Costafrolaz

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 64(7)

Published: Nov. 25, 2024

Peripheral modification is often the main approach to optimize natural products for improved biological activity or desired physicochemical properties. This procedure inevitably increases molecular weight, accompanied by undesired increased lipophilicity. Removing structural elements from not always tolerated. also case antibiotic fidaxomicin (Fdx), where every component has been shown be crucial activity. In this work, we demonstrate how residue switching can maintain of Fdx derivatives replacing rhamnoside-dichlorohomoorsellinate moiety with smaller, more polar building blocks. We used palladium-catalysed allylic substitution selectively install N-nucleophiles on core Fdx. The new were designed mimic binding bacterial RNA polymerase. Evaluation against Mycobacterium tuberculosis, Clostridioides difficile, and Gram-negative model organism Caulobacter crescentus demonstrated that newly introduced residues restore activity, which was further supported on-target polymerase assays. combined an organocatalysed novioside acylation protocol enable functionalisation two vectors in one pot. platform greatly expands accessible chemical space enables future development systemic antibiotics.

Language: Английский

Citations

1