title: Total synthesis and structure-activity relationships of new echinocandin-like antifungal cyclolipohexapeptides.
abstract: A series of new echinocandin-like cyclolipohexapeptides were designed and total synthesized via solution phase [3 + 3]-segment coupling strategy with an attempt to improve antifungal activity. The designed compounds showed potent antifungal activities with broad spectrum. In particular, 11 compounds (i.e. 28a-e, 28g, 28i-j, 29a, 29c and 29e) showed better in vitro antifungal activities against Candida albicans or Aspergillus fumigatus than caspofungin. Moreover, the synthesized compounds provided new SAR information for the echinocandins. The findings in this work suggested that the "left" tripeptide segment of cyclolipohexapeptide scaffold might be a hydrophilic structural motif, whereas the "right" lipopeptide segment was preferred as a hydrophobic core. The amino acid component of the cyclolipohexapeptide scaffold could significantly affect the SAR of the side chains.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Hongming
authors.initials: H
authors.lastname: Liu
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Hai
authors.initials: H
authors.lastname: Chen
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects*; D000077336:Caspofungin; D015195:Drug Design; D054714:Echinocandins / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D055666:Lipopeptides / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010456:Peptides, Cyclic; D000077336:Caspofungin