title: N-methylsansalvamide a peptide analogues. Potent new antitumor agents.
abstract: Sansalvamide A, a cyclic depsipeptide isolated from a marine fungus of the genus Fusarium, is composed of four hydrophobic amino acids (Phe, two Leu, Val) and one hydroxy acid ((S)-2-hydroxy-4-methylpentanoic acid; O-Leu) with five stereogenic centers all having S-stereochemistry. We have recently synthesized the corresponding cyclic peptide (Gu, W.; Liu, S.; Silverman, R. B. Organic Lett. 2002, 4, 4171-4174) and found that it too has antitumor activity. N-Methylation can enhance potency and selectivity for peptides. Consequently, here we synthesize 12 different N-methylated sansalvamide A peptide analogues and show that for several different tumor cell lines three of these analogues are more potent than the natural product; in pancreatic cells, sansalvamide A shows little activity, but the N-methylsansalvamide peptides are potent cytotoxic agents.
authors.affiliation: Department of Chemistry, and the Drug Discovery Program, Northwestern University, Evanston, Illinois 60208-3113, USA.
authors.forename: Shouxin
authors.initials: S
authors.lastname: Liu
authors.forename: Wenxin
authors.initials: W
authors.lastname: Gu
authors.forename: Denise
authors.initials: D
authors.lastname: Lo
authors.forename: Xian-Zhong
authors.initials: XZ
authors.lastname: Ding
authors.forename: Michael
authors.initials: M
authors.lastname: Ujiki
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Adrian
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Soff
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C119376:sansalvamide A