Thirty-one Sansalvamide A peptide derivatives were synthesized. (3)H thymidine inhibition assays were performed using two pancreatic cancer cell lines (PL45 and BxPC-3). Six compounds possess 140-fold increased differential selectivity for cancer cell lines over normal cell lines (WS1, skin fiberblasts) and are 140 times more active against pancreatic cancer cell lines than compounds used clinically to treat these cancers (e.g., 5-FU). Structure-activity relationship studies show the inclusion of a single N-methyl and/or d-amino acid appears to be critical for presenting the active conformation of the six San A peptide derivatives to their biological target(s).