Alanine scan-guided synthesis and biological evaluation of analogues of culicinin D, a potent anticancer peptaibol.

Abstract

Culicinin D (1), a 10 amino acid peptaibol originally isolated from Culicinomyces clavisporus, exhibits potent activity against a range of cancer cell lines. Building on our previous work exploring the structure-activity relationship (SAR) of the unusual (2S,4S,6R)-AHMOD residue, a series of analogues of culicinin D were prepared to further investigate the SAR of these peptaibols. Alanine scanning of a potent and readily accessible analogue 23 revealed the effect of each residue on antiproliferative activity, and a small panel of analogues were prepared to explore the SAR of the non-natural amino acid residue (2S,4R)-AMD. Results from the alanine scan were used to design an expanded library of culicinin D analogues, leading to the discovery of cyclohexylalanine analogue 52, which exhibited better antiproliferative activity than the natural product 1.

• Authors: Iman Kavianinia, Louise A Stubbing, Maria R Abbattista, Paul W R Harris, Jeff B Smaill, Adam V Patterson, Margaret A Brimble
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 30 Issue 11 Pg. 127135 (06 01 2020) ISSN: 1464-3405 [Electronic] England
• PMID: 32229061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Oligopeptides
• Peptaibols
• culicinin D
• Alanine

Topics

• Alanine (chemistry)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Hypocreales (chemistry, metabolism)
• Oligopeptides (chemical synthesis, chemistry, pharmacology)
• Peptaibols (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship