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Title: Selectivity improvement of an azole inhibitor of CYP707A by replacing the monosubstituted azole with a disubstituted azole.
Authors: Todoroki, Yasushi
Naiki, Kumi
Aoyama, Hikaru
Shirakura, Minaho
Ueno, Kotomi
Mizutani, Masaharu
Hirai, Nobuhiro
Journal Title: Bioorganic & Medicinal Chemistry Letters
Publisher: Elsevier
Journal Volume: 20
Journal Issue: 18
Start Page: 5506
End Page: 5509
Issue Date: 2010-09-15
Rights: Copyright © 2010 Elsevier Ltd All rights reserved.
NDC: 471
Description: The plant growth-retardant uniconazole (UNI), a triazole inhibitor of gibberellin biosynthetic enzyme (CYP701A), inhibits multiple P450 enzymes including ABA 8'-hydroxylase (CYP707A), a key enzyme in ABA catabolism. Azole P450 inhibitors bind to a P450 active site by both coordinating to the heme-iron atom via sp2 nitrogen and interacting with surrounding protein residues through a lipophilic region. We hypothesized that poor selectivity of UNI may result from adopting a distinct conformation and orientation for different active sites. Based on this hypothesis, we designed and synthesized novel UNI analogs with a disubstituted azole ring (DSI). These analogs were expected to have higher selectivity than UNI because the added functional group may interact with the active site to restrict orientation of the molecule in the active site. DSI-505ME and DSI-505MZ, which have an imidazolyl group with a methyl 5-acrylate, strongly inhibited recombinant CYP707A3, with no growth-retardant effect.
ISSN: 0960894X OPAC
E-ISSN: 14643405 OPAC
Publisher's DOI: 10.1016/j.bmcl.2010.07.067   
PMID: 20692835
Journal NCID: AA1079577X OPAC ciniib
Textversion: author
Appears in Collections:06. 雑誌論文・記事(Journal Article, Article, Preprint)

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Others By: Todoroki, Yasushi (轟, 泰司) (トドロキ, ヤスシ) -- Naiki, Kumi -- Aoyama, Hikaru -- Shirakura, Minaho -- Ueno, Kotomi -- Mizutani, Masaharu -- Hirai, Nobuhiro

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