Synthesis of Sansalvamide A derivatives and their cytotoxicity in the MSS colon cancer cell line HT-29.
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.
Styers
Thomas J
TJ
Department of Chemistry and Biochemistry, San Diego State University, CA 92182-1030, USA.
Kekec
Ahmet
A
Rodriguez
Rodrigo
R
Brown
Joseph D
JD
Cajica
Julia
J
Pan
Po-Shen
PS
Parry
Emily
E
Carroll
Chris L
CL
Medina
Irene
I
Corral
Ricardo
R
Lapera
Stephanie
S
Otrubova
Katerina
K
Pan
Chung-Mao
CM
McGuire
Kathleen L
KL
McAlpine
Shelli R
SR
D000596:Amino Acids / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000473:pathology; D047630:Depsipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D019073:HT29 Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000596:Amino Acids; D000970:Antineoplastic Agents; D047630:Depsipeptides; C119376:sansalvamide A; D013936:Thymidine