19/10/2017 · Total Synthesis of Vancomycin—Part 4: ..

We have reported the first stepwise substitution of the four phenols of vancomycin aglycon, defining a rank-order alkylation and indicating each phenol has a distinct reactivity, that was used to prepare a series of key partially methylated derivatives of the vancomycin aglycon. This series was utilized to further define the contribution methyl substitution of the phenols makes in a unique series of glycopeptide antibiotic derivatives that are active against vacomycin sensitive and resistant bacteria.

Several total syntheses of vancomycin aglycon have ..

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key methyl ether derivatives of vancomycin aglycon

Hamideh Zarrinmayeh, 1992. (Purdue University, Department of Chemistry) Thesis: "I. Evaluation of the Noncovalent Binding Selectivity of The Antitumor Antibiotic (+)-CC-1065. II. Use of an Alternative Strategy for Generation of Singly 5'-32P End-labeled Double-stranded DNA for Evaluation of the DNA Alkylation Properties of (+)-CC-1065 Functional Analogs. III. Evaluation of the Antitumor Antibiotics, Duocarmycins/Pyrindamycins, and their Functional Analogs. IV. An Alternative Preparation of a Key Intermediate Employed in the Synthesis of the Left-hand Subunit of (+)-CC-1065." Current Position: Research Scientist, Eli Lilly, Indianapolis, Indiana (1992-present).

The total synthesis of the glycopeptide antibiotics is ..

A select series of methyl ether derivatives of vancomcyin aglycon were prepared and examined for antimicrobial activity against vancomycin-sensitive Staphylococcus aureus and vancomycin-resistant Enterococci faecalis, as well as their binding affinity for D-Ala-D-Ala and D-Ala-D-Lac. The intent of the study was to elucidate the role selected key methyl groups may play in the improvement of in vitro antimicrobial profile of the tetra methyl ether derivative of vancomycin aglycon against vancomycin-resistant Enterococci faecalis previously reported. In these studies, methodology for selective derivatization of the A-, B-, and D-ring was developed that defines the relative reactivity of the four phenols of vancomycin aglycon, providing a foundation for future efforts for site-directed modification of the vancomycin aglycon core.

Total Synthesis of Vancomycin Analogs---Fighting Bacterial Resistance ..
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Total Synthesis of Vancomycin—Part 4: ..

501. C. M. Crane, J. G. Pierce, S. S. F. Leung, J. Tirado-Rives, W. L. Jorgensen, and D. L. Boger, Synthesis and evaluation of selected key methyl ether derivatives of vancomycin aglycon, J. Med. Chem.2010, 53, 7229-7235.

Total Synthesis of the Vancomycin Aglycon ..

467. C. M. Crane and D. L. Boger, Synthesis and evaluation of vancomycin aglycon analogues that bear modifications in the N-terminus D-leucyl amino acid, J. Med. Chem. 2009, 52, 1471-1476.

generation total synthesis of the teicoplanin aglycon.

Extending this to an interpretation of the resistant VanB E. faecalis results only requires that the organism remain sensitive to the hydrophobic vancomycin aglycon derivatives, but lose their sensitivity to the hydrophilic derivatives and those of intermediate hydrophilic character (40–100 fold). Finally, only the most hydrophobic derivative 6 retains activity against resistant VanA E. faecalis, albeit at a reduced level, whereas the other derivatives were inactive. The only exception to this latter trend was 13, which was 200-fold less active against resistant VanA E. faecalis than sensitive S. aureus. A simple interpretation of this behavior is that such hydrophobic derivatives of vancomycin aglycon fail to effectively trigger the inducible resistance mechanism resulting in the switch of peptidoglycan precursor from D-Ala-D-Ala to D-Ala-D-Lac. Evidence has been disclosed to indicate that this sensing of the glycopeptide challenge can arise from cell surface receptor recognition of either the antibiotic itself or the build-up of a bacterial cell wall biosynthetic intermediate by a two-component signaling pathway. Independent of the mechanism, the results herein suggest that the hydrophobic permethylated vancomycin aglycon derivatives, and the related teicoplanin and ristocetin aglycon methyl ethers, act by binding to D-Ala-D-Ala, fail to induce the resistance pathway resulting in D-Ala-D-Lac peptidoglycan generation, and serve as a distinct class of glycopeptide antibiotics effective against resistant bacteria.