title: Relationship between structure and biological activity of novel R106 analogs.
abstract: The retro-aldol reaction at residue 8 of R106-1 produced a chemical handle, in the form of a sarcosine residue, that was amenable to classical aldol alkylation conditions. In vitro assay of several new hydroxylated analogs have shown that L isomers exhibit more potent antifungal activity than D isomers. However, all analogs exhibited a significant decrease in activity against Cryptococcus neoformans. By contrast, structural modifications of R 106 were tolerated by some Candida spp., but the potency of activity was diminished as compared to that of the natural product R106-1. The full structure-activity relationship of the new R106 analogs has provided important information about the steric and electronic requirements of binding to target receptors. Furthermore, comparison of the structural differences between R106-1 and other derivatives, suggested that the potential for hydrogen bonding (at residue 8) was a key structural feature that was required to maintain activity against Cryptococcus neoformans.
authors.affiliation: Infectious Disease Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Rodriguez
authors.forename: M J
authors.initials: MJ
authors.lastname: Zweifel
authors.forename: J D
authors.initials: JD
authors.lastname: Farmer
authors.forename: R S
authors.initials: RS
authors.lastname: Gordee
authors.forename: R J
authors.initials: RJ
authors.lastname: Loncharich
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010455:Peptides; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D010455:Peptides; C096018:LY 295337