Synthesis of gem-difluorinated nucleoside analogues of the liposidomycins and evaluation as MraY inhibitors.
Two gem-difluoromethylenated nucleoside moieties of liposidomycins, 3 and 4, were designed and synthesized. Compound 3 was assembled from lactol 5 and gem-difluoromethylenated nucleoside 6. In the synthesis of target molecule 4, the coupling of the trichloroacetimidate derivative of gem-difluoromethylenated furanose 7 with nucleoside 8 in the presence of TMSOTf gave the unexpected compound 16 when CH3CN was used as solvent. This results from acetonitrile acting as a nucleophile and participating in the glycosylation reaction. This unusual process may be correlated with the presence of the electron-withdrawing gem-difluoro substituents at the C-2 position of furanose. Compound 3 demonstrated 29% inhibition of MraY at 11.4 mM.
Xu
Xiu-Hua
XH
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 354 Fenglin Lu, Shanghai 200032, China.
Trunkfield
Amy E
AE
Bugg
Timothy D H
TD
Qing
Feng-Ling
FL
D000617:Aminoglycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011854:Radiochemistry; D014166:Transferases / Q000037:antagonists & inhibitors*; D017855:Transferases (Other Substituted Phosphate Groups)
D000617:Aminoglycosides; D001426:Bacterial Proteins; D009705:Nucleosides; C047544:liposidomycins; D014166:Transferases; D017855:Transferases (Other Substituted Phosphate Groups); C079803:mraY protein, Bacteria