Derivatives of a novel cyclopeptolide. 1. Synthesis, antifungal activity, and structure-activity relationships.
The synthesis of a series of derivatives of the novel antifungal cyclopeptolide 1, which consists of nine S-amino acids and R-lactic acid, is described. Besides functional group variation of MeAsp4 (esters 2a-d, amides 3a-d, alcohol 4, and its derivatives) and Tyr(Me)9 (demethyl derivative 8, ethers 12a-f, 13, and oxidative degradation of the phenyl group to 14), opening of the lactone by LiOH in THF/H2O allowed manipulation of the hydroxy group of R-Hypr10 in the resulting acyclic peptide 15. Recyclization of 15 under Mitsunobu conditions followed by deprotection led to the S-Hypr10 analogue 17 of 1. Cyclic decapeptides 33 and 34 as well as cyclic undecapeptides 35 and 36 were obtained via the corresponding modified linear peptides 23, 24, 27, and 28 by cyclization. Methylation of all secondary amide groups by CH3I and KH/18crown6 gave the permethylated compound 37. Two of the derivatives (17 and 34) showed superior activities against yeasts in vitro at pH 6.5 as compared to 1, but not at a lower pH (4.5).
Department of Dermatology, SANDOZ Forschungsinstitut, Vienna, Austria.
G
G
Emmer
M A
MA
Grassberger
J G
JG
Meingassner
G
G
Schulz
M
M
Schaude
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002175:Candida / Q000187:drug effects; D002181:Candidiasis, Vulvovaginal / Q000188:drug therapy; D005260:Female; D007274:Injections, Intraperitoneal; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D010456:Peptides, Cyclic; C088262:cyclopeptolide 1