Applications of innovative synthetic strategies in anticancer drug Discovery: The Driving Force of new chemical reactions

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 119, P. 130096 - 130096

Published: Jan. 9, 2025

Language: Английский

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Development of cyclopeptide inhibitors specifically disrupting FXR-coactivator interaction in the intestine as a novel therapeutic strategy for MASH

Life Metabolism, Journal Year: 2025, Volume and Issue: 4(2)

Published: Feb. 7, 2025

Intestinal farnesoid X receptor (FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of dysfunction-associated steatohepatitis (MASH). All reported FXR target ligand-binding pocket (LBP) receptor, whereas antagonist acting on non-LBP site nuclear (NR) is conceived as a promising strategy discover novel antagonist. Here, we postulated hypothesis antagonizing by disrupting interaction between and coactivators, successfully developed series macrocyclic peptides based this premise. The cyclopeptide DC646 not only exhibits potent inhibitory activity FXR, but also demonstrates high degree selectivity towards other NRs. Moreover, has potential therapeutic benefit MASH an intestinal FXR-dependent manner, along with commendable safety profile. Mechanistically, distinct from known antagonists, specifically binds coactivator binding which can block recruitment, reducing circulation intestine-derived ceramides liver, promoting release glucagon-like peptide-1 (GLP-1). Overall, identify that targets FXR-coactivator interaction, paving way new approach treating antagonists.

Language: Английский

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Late-Stage Stitching Enabled by Palladium-Catalyzed Tryptophan C4 Amination: Peptide Ligation and Cyclodimerization

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Here, we report on methods for late-stage peptide diversification through palladium-catalyzed site-selective C(sp2)–H amination of tryptophan residues at the C4 position, utilizing tryptophan-amine cross-links. Our strategy enables practical access to C–N bonds, facilitating construction cyclopeptides via cyclodimerization structurally complex peptides, which poses significant challenges organic synthesis. The synthetic utility this protocol is demonstrated synthesis 30- 38-membered macrocyclic peptides.

Language: Английский

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Ruthenium(II)‐Catalyzed Pyridyl‐Directed Tryptophan C‐H Acylmethylation with α‐Chloro Ketones

Advanced Synthesis & Catalysis, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 22, 2024

Abstract A ruthenium(II)‐catalyzed C−H acylmethylation of Trp‐containing peptides with α ‐chloro ketones is reported here. This reaction features good C‐2 selectivity and chemoselectivity, making it suitable for late‐stage modification peptides. Low‐cost metal ruthenium as a catalyst enables the to be conducted on gram scale. report also discusses synthetic applications presents method remove pyridine directing group. In addition, plausible mechanism C(2)−H proposed in this article.

Language: Английский

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