Synthesis and antifungal activities of glycosylated derivatives of the cyclic peptide fungicide caspofungin.
Diseases caused by systemic fungal infections have become a significant clinical problem in recent decades. A series of glycosyl derivatives of the approved cyclic peptide antifungal drug caspofungin conjugated with β-D-glucopyranose, β-D-galactopyranose, β-D-xylopyranose, β-L-rhamnopyranose, β-maltose and β-lactose units were designed, synthesized, and evaluated as new potential antifungal drugs. The compounds were obtained by coupling the corresponding glycosyl amines to the free primary amino groups of caspofungin through a bifunctional glutaryl linker. In contrast to caspofungin, these glycosylated derivatives are soluble in water, but are not hygroscopic and moreover, are more stable than caspofungin under high humidity and temperature. CD studies showed that glycosylation has very little impact on the conformation of the cyclic peptide of caspofungin. In vitro antifungal tests against seven human pathogenic fungi revealed that the caspofungin-monosaccharide conjugates, but not the disaccharide conjugates, have increased antifungal activities against the majority of tested fungus species relative to caspofungin. The β-D-glucopyranosyl derivative 2 a showed the strongest and broadest antifungal activity, providing a lead for further studies.
Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Junxiang
J
Guo
Honggang
H
Hu
Qingjie
Q
Zhao
Ting
T
Wang
Yan
Y
Zou
Shichong
S
Yu
Qiuye
Q
Wu
Zhongwu
Z
Guo
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077336:Caspofungin; D002942:Circular Dichroism; D054714:Echinocandins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects; D006031:Glycosylation; D006813:Humidity; D055666:Lipopeptides; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013696:Temperature
D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010456:Peptides, Cyclic; D000077336:Caspofungin