Design and synthesis of potential mechanism-based inhibitors of the aminotransferase BioA involved in biotin biosynthesis

J Org Chem. 2012 Jul 20;77(14):6051-8. doi: 10.1021/jo3008435. Epub 2012 Jul 3.

Abstract

BioA, a pyridoxal 5'-phosphate (PLP) dependent aminotransferase, catalyzes the second step of biotin biosynthesis, converting 7-keto-8-aminopelargonic acid (KAPA) into 7,8-diaminopelargonic acid (DAPA). Amiclenomycin (ACM) isolated from cultures of different Streptomyces strains is a potent mechanism-based inhibitor of BioA that operates via an aromatization mechanism, irreversibly labeling the PLP cofactor. However, ACM is plagued by inherent chemical stability. Herein we describe the synthesis of four inhibitors, inspired by ACM but containing an allylic amine as the chemical warhead, designed to both improve stability and operate via a complementary Michael addition-pathway upon enzymatic oxidation of the allylic amine substrate to an enimine. Acyclic analogue M-1 contains a terminal olefin as the pro-Michael acceptor. The synthesis of M-1 features an alkyne-zipper reaction and the Overman rearrangement as key synthetic operations. The cyclic analogues M-2/3/4 contain either an endocyclic or exocyclic olefin as the pro-Michael acceptor. These were all prepared using a common strategy employing DIBAL reduction of a precursor bicyclic lactam, followed by in situ Horner-Wadsworth-Emmons (HWE) olefination as the key synthetic steps.

Publication types

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

MeSH terms

  • Aminobutyrates / chemical synthesis
  • Aminobutyrates / chemistry
  • Aminobutyrates / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Biocatalysis
  • Biotin / biosynthesis
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Molecular Structure
  • Mycobacterium tuberculosis / enzymology
  • Streptomyces / chemistry
  • Structure-Activity Relationship
  • Transaminases / antagonists & inhibitors*
  • Transaminases / chemistry
  • Transaminases / metabolism

Substances

  • Aminobutyrates
  • Bacterial Proteins
  • Enzyme Inhibitors
  • amiclenomycin
  • Biotin
  • Transaminases
  • BioA protein, bacteria