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

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 (2 S ,4 S ,6 R)-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 (2 S ,4 R)-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. [ABSTRACT FROM AUTHOR]