Total synthesis and examination of three key analogues of ramoplanin: a lipoglycodepsipeptide with potent antibiotic activity.
The total synthesis and evaluation of three key ramoplanin aglycon analogues are detailed. The first (5a) represents replacement of the labile depsipeptide ester with a stable amide (HAsn2 --> Dap2) with removal of the HAsn pendant carboxamide, and it was found to be slightly more potent than the natural aglycon in antimicrobial assays providing a new lead structure with an improved profile and a more stable and accessible macrocyclic template on which to conduct structure-function studies. In contrast, a second amide analogue 5b which contains a single additional methylene relative to 5a (HAsn2 --> Dab2) was found to be inactive in antimicrobial assays (>100-fold loss in activity). The third key analogue 5c in which the Asn1 lipid side chain was replaced with an acetyl group revealed that it contributes significantly to the antimicrobial activity (16-fold) of the ramoplanins, but is not essential.
Rew
Yosup
Y
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Shin
Dongwoo
D
Hwang
Inkyu
I
Boger
Dale L
DL
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047630:Depsipeptides; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D047630:Depsipeptides; D006020:Glycopeptides; D010456:Peptides, Cyclic; C041438:ramoplanin