43.ABA 8'-水酸化酵素に対する実用性の高い選択的阻害剤アブシナゾールE2B(口頭発表)

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Uniconazole (UNI), which was developed as an inhibitor of GA biosynthetic enzyme (CYP701A), is a low selective P450 inhibitor that inhibits multiple P450 enzymes including abscisic acid (ABA) 8'-hydroxylase (CYP707A). Based on our speculation that the low selectivity of UNI may be resulted from its small molecule, we developed enlarged UNI analogues (UT) that have a 1,2,3-triazolyl alkyl chain. Although UT compounds showed the strong CYP707A inhibition, the biological activity of most of UT compounds was not tested because of their water-insolubility. Because the introduction of protic functional groups in the alkyl chain diminished the inhibitory activity, we developed Abz-E1 that has a diethylene glycol chain with a terminal tosylate. Abz-E1 showed good water solubility and strong inhibitory activity against CYP707A in vitro and in vivo. Because Abz-E1 has a terminal tosylate, it is expected to be useful precursor for multifunctional chemical probes. Because of the same reason, however, Abz-E1 seems to be unstable in vivo. Thus we synthesized four compounds from Abz-E1 to examine the requirement of the tosylate for CYP707A inhibition and to generate a new practical CYP707A inhibitor. The results showed that the tosylate is not necessary for the inhibition, whereas the hydrophobicity is more significant for it than the molecular length. Finally we found a more practical inhibitor of CYP707A, abscinazole-E2B (Abz-E2B), with no tosylate and with good water solubility.
2010-10-01

43.ABA 8'-水酸化酵素に対する実用性の高い選択的阻害剤アブシナゾールE2B(口頭発表)

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