Synthesis of new analogs of echinocandin B by enzymatic deacylation and chemical reacylation of the echinocandin B peptide: synthesis of the antifungal agent cilofungin (LY121019).
The antifungal antibiotic, echinocandin B (ECB), was modified by a sequential procedure in which the initial step involved enzymatic removal of the native N-linoleoyl group from the N-terminus using an Actinoplanes utahensis culture. The resulting product, ECB nucleus, was reacylated using active esters or acid halides of various substituted acids to give a series of ECB analogs. These analogs possessed anti-Candida activity both in vitro and in vivo (mice). Other studies have shown that one of these, cilofungin, the 4-n-octyloxybenzoyl-ECB analog (LY121019), has excellent anti-Candida activity, low toxicity and is superior to other available antifungal antibiotics.
Debono
M
M
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Abbott
B J
BJ
Fukuda
D S
DS
Barnhart
M
M
Willard
K E
KE
Molloy
R M
RM
Michel
K H
KH
Turner
J R
JR
Butler
T F
TF
Hunt
A H
AH
D000215:Acylation; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents / Q000138:chemical synthesis*; D054714:Echinocandins; D005656:Fungal Proteins; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D010456:Peptides, Cyclic; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D010455:Peptides; D010456:Peptides, Cyclic; C042101:cilofungin; C007572:echinocandin B