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The total synthesis of depsipeptide antibiotics

Abstract

The use of antibiotics has greatly impacted the treatment of bacterial infections since there introduction in the 1940's. However, the selective pressures caused by the widespread use of antibiotics have resulted in the emergence of resistant bacteria, decreasing the therapeutic efficiency of many classes of chemotherapeutic agents. Nature's ability to select for resistance pathogens has resulted in the need to replace obsolete antibiotics with new ones functioning via different modes of action. In recent years, we have seen a renewed interest in the isolation of natural products with antibiotic activity and has led to the discovery of new molecular platforms for development potent analogs and/or semi-synthetic derivatives. Our focus has been directed toward the chemical synthesis and mechanistic studies of new peptide antibiotics that show potential as alternative treatments for bacterial infections arising from resistant bacteria. Plusbacin A3 and WAP-8294A2 are lipodepsipeptide antibiotics isolated from the culture broths of Psuedomonas and Lysobacter, respectively. Both natural products are active against a diverse panel of gram positive bacteria. In particular they have been shown to exhibit potent in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci. Our goal was to develop a convergent total synthesis for each antibiotic and to carry out structure activity relationships in order to study their mechanism of action. We have successfully completed the first total synthesis and stereochemical assignment of plusbacin A3. We accomplished the stereoselective synthesis of a variety of non-proteogenic amino acids including an innovative route for preparation of both Boc-[beta]OBn-D-Asp(OCy)-OH and Boc-[beta]OBn-L- Asp(OCy)-OH. An efficient synthesis of Boc-D-allo-Thr-OH was utilized to provide ample material for our synthetic effort. Both stereochemical configurations of the allyl 3- hydroxy-14-methylpentadecanoate were accessed through the key lipase resolution. With the total synthesis of plusbacin A3 complete, our attention was then directed to a mechanistic analysis of this promising antibiotic. A conformational analysis using 2D NMR with molecular modeling provided a solution structure of plusbacin A3 and was used to design and series of analogs to analyze structure activity relationships (SARs). Several analogs were synthesized to examine the importance of key structural elements. Biological assays of the analogs determining the minimum inhibitory concentrations revealed that the hydrophobic lipid chain of plusbacin was essential for antibacterial activity. The arginine moiety was determined to play an important role in the stabilization of the plusbacin A3 active conformation. The modification of several residues that were believed to participate in stabilizing hydrogen bonding interactions were also examined. Although many of the analogs showed a decreased, or complete loss of activity, the initial SAR studies provided important mechanistic information about the mode of action. The first total synthesis of WAP- 8294A2 was accomplished via the enantioselective synthesis of a several non-proteogenic amino acids and their incorporation into the peptide backbone. The later stages of the synthesis employed solid phase peptide synthesis (SPPS) which allowed for the efficient acylations of a variety of N-methyl amino acids and a strategic on-resin macrocyclization reaction. The convergent total synthesis of the promising antibiotic has set the stage for important mechanistic and SAR studies

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