54.配座固定とアゾール環修飾による高選択性アゾール系植物P450阻害剤の創製(口頭発表)

概要

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Uniconazole (UNI), which is well known as a triazole-containing inhibitor of ent-kaurene oxidase, functions as a very strong inhibitor of ABA 8'-hydroxylase, CYP707A. Azole-containing P450 inhibitors bind to a P450 active site by both coordinating to the heme-iron atom via sp2 nitrogen and interactioning with surrounding protein residues through the lipophilic region. We speculated that poor selectivity of UNI may be resulted from its flexibile conformation adjustable for a variety of substrate pockets. Based on this speculation, we designed and synthesized conformationally restricted UNI analogues, which are expected to have higher selectivity than UNI. The rigid analogues were examined the selectivity in the enzyme and plant growth assays. We also examined synthetic intermediate whose azole ring was modified. UFAP1 and IFAP2, which were restricted differently, showed contrasting results. UFAP1 did not inhibit CYP707A, but inhibited growth of rice. On the other hand, IFAP2 strongly inhibited CYP707A, but did not inhibit growth of rice. This suggests that the conformational restriction may improve the enzyme specificity of UNI. We are examining other conformationally-rigid and azole-modified analogues.
2008-10-06