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  Design, synthesis, and evaluation of 6-carboxyalkyl and 6- phosphonoxyalkyl derivatives of 7-oxo-8-ribitylaminolumazines as inhibitors of riboflavin synthase and lumazine synthase

Cushman, M., Yang, D. L., Gerhardt, S., Huber, R., Fischer, M., Kis, K., et al. (2002). Design, synthesis, and evaluation of 6-carboxyalkyl and 6- phosphonoxyalkyl derivatives of 7-oxo-8-ribitylaminolumazines as inhibitors of riboflavin synthase and lumazine synthase. Journal of Organic Chemistry, 67(16), 5807-5816.

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Genre: Journal Article
Alternative Title : J. Org. Chem.

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 Creators:
Cushman, M., Author
Yang, D. L., Author
Gerhardt, S.1, Author              
Huber, R.2, Author              
Fischer, M., Author
Kis, K., Author
Bacher, A., Author
Affiliations:
1External Organizations, ou_persistent22              
2Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              

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 Abstract: A series of 6-carboxyalkyl and 6-phosphonoxyalkyl derivatives of 7-oxo-8-D-ribityllumazine were synthesized as inhibitors of both Escherichia coli riboflavin synthase and Bacillus subtilis lumazine synthase. The compounds were designed to bind to both the ribitylpurine binding site and the phosphate binding site of lumazine synthase. In the carboxyalkyl series, maximum activity against both enzymes was observed with the 3'- carboxypropyl compound 22. Lengthening or shortening the chain linking the carboxyl group to the lumazine by one carbon resulted in decreased activity. In the phosphonoxyalkyl series, the 3'-phosphonoxypropyl compound 33 was more potent than the 4'-phosphonoxybutyl derivative 39 against lumazine synthase, but it was less potent against riboflavin synthase. Molecular modeling suggested that the terminal carboxyl group of 6- (3'carboxypropyl)-7-oxo-8-D-ribityllumazine (22) may bind to the side chains of Arg127 and Lys135 of the enzyme. A hypothetical molecular model was also constructed for the binding of 6-(2'carboxyethyl)-7-oxolumazine (15) in the active site of E. coli riboflavin synthase, which demonstrated that the active site could readily accommodate two molecules of the inhibitor.

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Language(s): eng - English
 Dates: 2002-08-09
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 41685
ISI: 000177318300045
 Degree: -

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Title: Journal of Organic Chemistry
  Alternative Title : J. Org. Chem.
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 67 (16) Sequence Number: - Start / End Page: 5807 - 5816 Identifier: ISSN: 0022-3263