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Synthesis and evaluation of vancomycin aglycon analogues that bear modifications in the N-terminal D-leucyl amino acid.

ABSTRACT: The synthesis and biological evaluation of a series of vancomycin aglycon analogues bearing alternative residue 1 N-methyl-D-amino acids are described. The analogues were prepared to define whether H-bonding d-amino acids could improve the affinity for the model ligands N,N'-Ac(2)-L-Lys-D-Ala-D-Ala (2) and N,N'-Ac(2)-L-Lys-D-Ala-D-Lac (3) and improve antimicrobial activity against vancomycin-sensitive or vancomycin-resistant bacteria. Additionally, a series of analogues with appended nucleophiles (hydrazines and amines) on the residue 1 D-amino acids are described that were examined for their ability to react with the C-terminal ester of 3, forming a covalent attachment of L-Lys-D-Ala to the natural product analogues.

SUBMITTER: Crane CM

PROVIDER: S-EPMC2765482 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Synthesis and evaluation of vancomycin aglycon analogues that bear modifications in the N-terminal D-leucyl amino acid.

Crane Christine M CM Boger Dale L DL

Journal of medicinal chemistry 20090301 5

The synthesis and biological evaluation of a series of vancomycin aglycon analogues bearing alternative residue 1 N-methyl-D-amino acids are described. The analogues were prepared to define whether H-bonding d-amino acids could improve the affinity for the model ligands N,N'-Ac(2)-L-Lys-D-Ala-D-Ala (2) and N,N'-Ac(2)-L-Lys-D-Ala-D-Lac (3) and improve antimicrobial activity against vancomycin-sensitive or vancomycin-resistant bacteria. Additionally, a series of analogues with appended nucleophile ...[more]

PMID: 19209892

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Project description:The total synthesis of [Ψ[C(═S)NH]Tpg(4)]vancomycin aglycon (8) and its unique AgOAc-promoted single-step conversion to [Ψ[C(═NH)NH]Tpg(4)]vancomycin aglycon (7), conducted on a fully deprotected substrate, are disclosed. The synthetic approach not only permits access to 7, but it also allows late-stage access to related residue 4 derivatives, alternative access to [Ψ[CH(2)NH]Tpg(4)]vancomycin aglycon (6) from a common late-stage intermediate, and provides authentic residue 4 thioamide and amidine derivatives of the vancomycin aglycon that will facilitate ongoing efforts on their semisynthetic preparation. In addition to early stage residue 4 thioamide introduction, allowing differentiation of one of seven amide bonds central to the vancomycin core structure, the approach relied on two aromatic nucleophilic substitution reactions for formation of the 16-membered diaryl ethers in the CD/DE ring systems, an effective macrolactamization for closure of the 12-membered biaryl AB ring system, and the defined order of CD, AB, and DE ring closures. This order of ring closures follows their increasing ease of thermal atropisomer equilibration, permitting the recycling of any newly generated unnatural atropisomer under progressively milder thermal conditions where the atropoisomer stereochemistry already set is not impacted. Full details of the evaluation of 7 and 8 along with several related key synthetic compounds containing the core residue 4 amidine and thioamide modifications are reported. The binding affinity of compounds containing the residue 4 amidine with the model D-Ala-D-Ala ligand 2 was found to be only 2-3 times less than the vancomycin aglycon (5), and this binding affinity is maintained with the model d-Ala-d-Lac ligand 4, representing a nearly 600-fold increase in affinity relative to the vancomycin aglycon. Importantly, the amidines display effective dual, balanced binding affinity for both ligands (K(a)2/4 = 0.9-1.05), and they exhibit potent antimicrobial activity against VanA resistant bacteria ( E. faecalis , VanA VRE) at a level accurately reflecting these binding characteristics (MIC = 0.3-0.6 μg/mL), charting a rational approach forward in the development of antibiotics for the treatment of vancomycin-resistant bacterial infections. In sharp contrast, 8 and related residue 4 thioamides failed to bind either 2 or 4 to any appreciable extent, do not exhibit antimicrobial activity, and serve to further underscore the remarkable behavior of the residue 4 amidines.

Dataset Information

Synthesis and evaluation of vancomycin aglycon analogues that bear modifications in the N-terminal D-leucyl amino acid.

Publications

Synthesis and evaluation of vancomycin aglycon analogues that bear modifications in the N-terminal D-leucyl amino acid.

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