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Synthesis of D-alanyl-D-alanine dipeptide isosteres and cephalosporin prodrugs




Gansle, Paul, Jr., author
Williams, Robert M., advisor

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Resistance to vancomycin by enterococci is of great clinical importance. Vancomycin inhibits bacterial growth by binding to terminal D-alanyl-D-alanine linkages in the growing peptidoglycan cell wall. Synthesis of dipeptide isosteres which may be incorporated into the growing cell wall is described. Previously published syntheses were employed as well as a Wittig reaction using a chiral Wittig reagent, a reaction not used in the synthesis of isosteres before. If the isosteres are directly incorporated, cell wall synthesis will be inhibited. Additionally, it is believed that the isosteres will act as mechanism-based inhibitors of the enzymes which are responsible for vancomycin resistance. Delivery of dipeptides into bacteria is difficult due to selective transport mechanisms. Several reports have been made which use a cephalosporin prodrug with a dual mode of action. Antibiotics are coupled to cephalosporin intermediates and produce a compound which is capable of acting as an antibiotic on its own as well as delivering the coupled antibiotic into the periplasm by enzymatic hydrolysis of the prodrug. A novel phase-transfer reaction was used to couple dipeptide isosteres to a cephalosporin intermediate.


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Organic compounds -- Synthesis


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