Site-selective photoredox reactions with aromatic olefins enable direct alkylation of unprotected myo-inositol at C4. The efficacy of these reactions can be finely tuned by modifying the structures of HAT reagents....
The rapid emergence of resistant bacteria and the scarcity of antibiotic pipeline has been a persistent threat to the global health. To expand the antibiotic pipeline, we have focused our strategy by revitalizing the current antibiotic via novel site-specific derivatization. Aminoglycosides (AGs), once considered effective therapeutics for treating clinical infections, are now seeing limited use due to drug-induced toxicity and AG-resistant bacteria. Challenges in synthesis and modifications of AGs impedes their potential for re-gaining efficacy. Here we discuss a photoredox catalyzed late-stage modification of glucosides including AGs. Our chemistry can selectively install an alkyl group at the 3- position of unprotected glucoside with a broad substrate scope and high yields. Among the products, we characterized a series of compounds that can overcome drug resistance caused by APH (3’) and one of them achieved 30-fold potency compared to kanamycin against sensitive strains. The chemistry we describe here opens a new avenue for discovering new AGs antibiotics that overcome drug resistance and may also serve as the basis for understanding their SARs.
The rapid emergence of resistant bacteria and the scarcity of antibiotic pipeline has been a persistent threat to the global health. To expand the antibiotic pipeline, we have focused our strategy by revitalizing the current antibiotic via novel site-specific derivatization. Aminoglycosides (AGs), once considered effective therapeutics for treating clinical infections, are now seeing limited use due to drug-induced toxicity and AG-resistant bacteria. Challenges in synthesis and modifications of AGs impedes their potential for re-gaining efficacy. Here we discuss a photoredox catalyzed late-stage modification of glucosides including AGs. Our chemistry can selectively install an alkyl group at the 3- position of unprotected glucoside with a broad substrate scope and high yields. Among the products, we characterized a series of compounds that can overcome drug resistance caused by APH (3’) and one of them achieved 30-fold potency compared to kanamycin against sensitive strains. The chemistry we describe here opens a new avenue for discovering new AGs antibiotics that overcome drug resistance and may also serve as the basis for understanding their SARs.
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