Synthesis of mono- and disaccharide analogs of moenomycin and lipid II for inhibition of transglycosylase activity of penicillin-binding protein 1b.
Three types of mono- and disaccharides 3a,b, 4a-c, 5, and some chaetomellic acid A analogs 6 and 42-44 were synthesized as potential inhibitors of the transglycosylase activity of penicillin-binding protein 1b (PBP1b), a key bacterial enzyme responsible for the formation of the polysaccharide backbone of peptidoglycan as well as for cross-linking of its peptide portions. The target compounds combine structural features of both the active portion of moenomycin and the natural PBP1b substrate, lipid II. The desired skeletons were obtained in a convergent fashion involving attachment of the lipid-alkylated glyceric acid moieties 11a,b to the corresponding carbohydrate-containing phosphonic acids 23, 24a, and 24b. Compounds 3a,b were prepared to verify the distance requirements between the sugar and the noncleavable C-phosphonate moieties. Compounds 4a-c were synthesized to examine the importance of the first sugar unit of moenomycin, a known inhibitor of transglycosylase catalysis by PBP1b, with respect to antibiotic activity. These were prepared by condensation of 11a,b with 28a and 28c, which were made by glycosylation of 3-bromopropanol with oxazolines 25a,b, and Arbuzov reaction with triethyl or trimethyl phosphite, followed by dealkylation with bromotrimethylsilane. Compound 5 was generated to verify the possibility of using a dicarboxylate group to mimic the diphosphate of lipid II. It was synthesized by coupling of alcohol 31 with alpha-trichloroacetimidate 34. Chaetomellic acid A analogs were prepared by a Michael addition to dimethyl acetylenedicarboxylate. With the exception of 3b, all of the target compounds were found to inhibit PBP1b, albeit with modest potency.
Garneau
Sylvie
S
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
Qiao
Lei
L
Chen
Lan
L
Walker
Suzanne
S
Vederas
John C
JC
D001455:Bambermycins / Q000138:chemical synthesis* / Q000494:pharmacology; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000494:pharmacology; D004187:Disaccharides / Q000138:chemical synthesis / Q000494:pharmacology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors; D006602:Hexosyltransferases / Q000037:antagonists & inhibitors*; D008298:Maleates / Q000138:chemical synthesis / Q000494:pharmacology; D009005:Monosaccharides / Q000138:chemical synthesis / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D002241:Carbohydrates; D004187:Disaccharides; D029968:Escherichia coli Proteins; D008298:Maleates; D009005:Monosaccharides; D046915:Penicillin-Binding Proteins; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; D001455:Bambermycins; C080569:chaetomellic acid A; D006602:Hexosyltransferases