Total synthesis and evaluation of [Psi[CH2NH]Tpg4]vancomycin aglycon: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding

J Am Chem Soc. 2006 Mar 8;128(9):2885-92. doi: 10.1021/ja0572912.

Abstract

An effective synthesis of [Psi[CH(2)NH]Tpg(4)]vancomycin aglycon (5) is detailed in which the residue 4 amide carbonyl of vancomycin aglycon has been replaced with a methylene. This removal of a single atom was conducted to enhance binding to D-Ala-D-Lac, countering resistance endowed to bacteria that remodel their D-Ala-D-Ala peptidoglycan cell wall precursor by a similar single atom change (ester O for amide NH). Key elements of the approach include a synthesis of the modified vancomycin ABCD ring system featuring a reductive amination coupling of residues 4 and 5 for installation of the deep-seated amide modification, the first of two diaryl ether closures for formation of the modified CD ring system (76%, 2.5-3:1 kinetic atropodiastereoselectivity), a Suzuki coupling for installation of the hindered AB biaryl bond (90%) on which the atropisomer stereochemistry could be thermally adjusted, and a macrolactamization closure of the AB ring system (70%). Subsequent DE ring system introduction enlisted a room-temperature aromatic nucleophilic substitution reaction for formation of the remaining diaryl ether (86%, 6-7:1 kinetic atropodiastereoselectivity), completing the carbon skeleton of 5. Consistent with expectations and relative to the vancomycin aglycon, 5 exhibited a 40-fold increase in affinity for D-Ala-D-Lac (K(a) = 5.2 x 10(3) M(-1)) and a 35-fold reduction in affinity for D-Ala-D-Ala (K(a) = 4.8 x 10(3) M(-1)), providing a glycopeptide analogue with balanced, dual binding characteristics. Beautifully, 5 exhibited antimicrobial activity (MIC = 31 microg/mL) against a VanA-resistant organism that remodels its D-Ala-D-Ala cell wall precursor to d-Ala-d-Lac upon glycopeptide antibiotic challenge, displaying a potency that reflects these binding characteristics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / analogs & derivatives*
  • Alanine / chemistry
  • Dipeptides / chemistry*
  • Dipeptides / metabolism
  • Kinetics
  • Lactates / chemistry
  • Lactates / metabolism
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Vancomycin / analogs & derivatives*
  • Vancomycin / chemical synthesis
  • Vancomycin / metabolism

Substances

  • Dipeptides
  • Lactates
  • Oligopeptides
  • alanylalanine
  • Vancomycin
  • Alanine