Design, synthesis and evaluation of cyclothialidine analogues as DNA gyrase inhibitors

  • Kylie M. Loak

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Cyclothialidine, a natural product isolated from Streptomyces .filipinensis
NR0484, has been proven to be a potent and selective inhibitor of the bacterial enzyme DNA gyrase. Gyrase inhibition results in cell death, the enzyme being the target of several currently used antibiotics. Cyclothialidine showed poor activity against whole bacterial cells, highlighting scope for improvement regarding cell membrane pemeability in order for the full potential of this new class of antibiotics to be realised,
Structurally, cyclothialidine contains a 12-membered lactone ring which is partly
integrated into a pentapeptide chain, with a substituted aromatic moiety bordering the lactone, Retrosynthetically it can be traced back to cis-3-hydroxyproline, 3,5-dihydroxy-2,6-dimethylbenzoic acid and four commercially available amino acids; two serine, one cysteine and one alanine.
In this work, a model of cyclothialidine was synthesised in order to establish the
methodology for more complex compounds. Analogues with hydroxy, dihydroxy and dihydroxymethyl substituted aromatic moieties were then prepared to ensure successful protection methods could be performed and the pharmacophore synthesised. The key
aromatic moiety, 2,6-dimethyl-3,5-dihydroxybenzoic acid was produced via two
successive Mannich reaction/reduction steps. Acid protection using 4-nitrobenzyl
bromide and TBDMS hydroxyl protection followed by bromination of one methyl
afforded the desired intermediate. Reaction with a serine/cysteine dipeptide, followed by deprotection and cyclisation under Mitsunobu conditions lead to the 12-membered lactone. An amine substituted aromatic analogue and also replacement of the cysteine sulphur by oxygen were attempted but without success.
In an effort to improve cell permeability, a conjugate was synthesised between the pharmacophore and a cholesterol moiety. It was hoped the steroid fragment would serve to increase potency by escorting the molecule through the lipid environment of the cell membrane. The pharmacophore and conjugate were tested against a variety of bacterial strains but the conjugate failed to improve activity.
Date of AwardSep 1999
LanguageEnglish
SupervisorYong F Wang (Supervisor)

Keywords

  • natural product
  • antibiotics
  • lactone
  • pharmacophore
  • conjugate

Cite this

Design, synthesis and evaluation of cyclothialidine analogues as DNA gyrase inhibitors
Loak, K. M. (Author). Sep 1999

Student thesis: Doctoral ThesisDoctor of Philosophy