A new non-azole inhibitor of ABA 8'-hydroxylase: effect of the hydroxyl group substituted for geminal methyl groups in the six-membered ring

Bioorg Med Chem Lett. 2006 Jun 15;16(12):3302-5. doi: 10.1016/j.bmcl.2006.03.024. Epub 2006 Mar 24.

Abstract

We designed and synthesized AHI4 that has an axial hydroxyl group instead of geminal methyl groups at C-6' of AHI1, previously reported as a lead compound for the development of non-azole inhibitors of ABA 8'-hydroxylase. (+)-AHI4 competitively inhibited 8'-hydroxylation of ABA by recombinant CYP707A3. The K(I) value was found to be 0.14 microM, 10-fold less than that of (+)-AHI1, suggesting that enzyme affinity increased by a factor of 10 due to substitution of the hydroxyl group by the geminal methyls at C-6'. This finding should assist in the design of more effective, non-azole ABA 8'-hydroxylase inhibitors.

MeSH terms

  • Azoles / chemistry
  • Azoles / pharmacology
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hydroxylation
  • Methylation
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / metabolism
  • Molecular Structure
  • Oryza / drug effects
  • Oryza / enzymology
  • Plant Proteins
  • Seedlings / drug effects
  • Seedlings / enzymology
  • Water

Substances

  • Azoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Plant Proteins
  • Water
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • abscisic acid 8'-hydroxylase