Mode of action of 4-hydroxyphenylpyruvate dioxygenase inhibition by triketone-type inhibitors.

Abstract:

:A series of 2-(2-nitrobenzoyl)cyclohexane-1,3-dione analogues (1-9) were designed, synthesized, and evaluated for inhibition of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), a key enzyme involved in the catabolism of tyrosine which catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. The correlations between the results of enzyme inhibition, ferric chloride tests, and the conformational analysis suggested that the tight binding between triketone-type inhibitors and 4-HPPD is likely due to chelation of the enzyme-bound ferric iron with the enol tautomer of 1,3-diketone moiety of the triketones. The presence of a 2-carbonyl group in the triketone is an essential structural feature for potent 4-HPPD inhibition. Modification of the 3-carbonyl group of triketone moiety to other functionality will reduce the overall planarity and thus prevent keto-enol tautomerization, resulting in a decrease or lack of inhibition activity.

journal_name

J Med Chem

authors

Wu CS,Huang JL,Sun YS,Yang DY

doi

10.1021/jm010568y

keywords:

subject

Has Abstract

pub_date

2002-05-23 00:00:00

pages

2222-8

issue

11

eissn

0022-2623

issn

1520-4804

pii

jm010568y

journal_volume

45

pub_type

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