Preparation and structure-activity relationships of simplified analogues of the antifungal agent cilofungin: a total synthesis approach.
The echinocandins are a well-known class of lipopeptides characterized by their potent antifungal activity against Candida species. The mechanism of action of the echinocandins is generally thought to be the inhibition of beta-1,3-glucan synthesis, an important structural component in the cell wall of Candida species. Extensive structure-activity studies on the fatty acid side chain of echinocandin B (1) led to the preparation of the clinical candidate cilofungin (4). However, little is known about the cyclic peptide. We now report the preparation, by solid-phase synthesis, of a series of simplified analogs of cilofungin in which the unusual amino acids found in the echinocandins were replaced with more readily accessible natural amino acids. The solid-phase approach to the total synthesis of these analogs allowed us to conveniently explore structural modifications that could not be accomplished by chemical modification of the natural product. The simplest analog 5 showed no biological activity. Structural complexity was then returned to the system in a systematic fashion so as to reapproach the original cilofungin structure. Antifungal activity and the inhibition of beta-1,3-glucan synthesis were monitored at each step of the process, thereby revealing the basic structure-activity relationships of the amino acids and the minimal structural requirements for biological activity in the echinocandin ring system. The results suggests that the 3-hydroxy-4-methylproline residue enhances activity but the L-homotyrosine residue is crucial for both antifungal activity and the inhibition of beta-1,3-glucan synthesis.
Zambias
R A
RA
Merck Research Laboratories, Rahway, New Jersey 07065.
Hammond
M L
ML
Heck
J V
JV
Bartizal
K
K
Trainor
C
C
Abruzzo
G
G
Schmatz
D M
DM
Nollstadt
K M
KM
D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002175:Candida / Q000187:drug effects; D054714:Echinocandins; D005936:Glucans / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D010456:Peptides, Cyclic; D013329:Structure-Activity Relationship; D047071:beta-Glucans
D000935:Antifungal Agents; D054714:Echinocandins; D005936:Glucans; D010455:Peptides; D010456:Peptides, Cyclic; D047071:beta-Glucans; C042101:cilofungin; C033363:beta-1,3-glucan