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

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 KI value was found to be 0.14 μM, 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.

The axial hydroxyl group at C-6′ stabilizes the enzyme–ligand complex more strongly than the geminal methyls.Figure optionsDownload as PowerPoint slide