Synthesis of Sansalvamide A derivatives and their cytotoxicity in the MSS colon cancer cell line HT-29

Abstract

We report the synthesis of thirty-six Sansalvamide A derivatives, and their biological activity against colon cancer HT-29 cell line, a microsatellite stable (MSS) colon cancer cell-line. The thirty-six compounds can be divided into three subsets, where the first subset of compounds contains l-amino acids, the second subset contains d-amino acids, and the third subset contains both d- and l-amino acids. Five compounds exhibited excellent inhibitory activity (>75% inhibition). The structure–activity relationship (SAR) of the compounds established that a single d-amino acid in position 2 or 3 gave up to a 10-fold improved cytotoxicity over Sansalvamide A peptide. This work highlights the importance of residues 2 and 3 and the role of d-amino acids in the extraordinary SAR for this compound class.