Author/Authors :
Thomas J. Styers، نويسنده , , Ahmet Kekec، نويسنده , , Rodrigo Rodriguez، نويسنده , , Joseph D. Brown، نويسنده , , Julia Cajica، نويسنده , , Po-Shen Pan، نويسنده , , Emily Parry، نويسنده , , Chris L. Carroll، نويسنده , , Irene Medina، نويسنده , , Ricardo Corral، نويسنده , , Stephanie Lapera، نويسنده , , Katerina Otrubova، نويسنده , , Chung-Mao Pan، نويسنده , , Kathleen L. McGuire، نويسنده , , Shelli R. McAlpine، نويسنده ,
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.
Keywords :
Macrocycles , Macrocyclic peptides , Cytotoxicity , Colon cancer , Peptides , MSS , Sansalvamide A