Discovery and Development of a Small Molecule Library with Lumazine Synthase Inhibitory Activity

Talukdar, Arindam; Breen, Megan; Bacher, Adelbert; Illarionov, Boris; Fischer, Markus; Georg, Gunda I.; Ye, Qi-Zhuang; Cushman, Mark

dc.contributor.author	Talukdar, Arindam
dc.contributor.author	Breen, Megan
dc.contributor.author	Bacher, Adelbert
dc.contributor.author	Illarionov, Boris
dc.contributor.author	Fischer, Markus
dc.contributor.author	Georg, Gunda I.
dc.contributor.author	Ye, Qi-Zhuang
dc.contributor.author	Cushman, Mark
dc.date.accessioned	2017-04-12T17:30:49Z
dc.date.available	2017-04-12T17:30:49Z
dc.date.issued	2009
dc.identifier.citation	Talukdar, A., Breen, M., Bacher, A., Illarionov, B., Fischer, M., Georg, G., … Cushman, M. (2009). Discovery and Development of a Small Molecule Library with Lumazine Synthase Inhibitory Activity. The Journal of Organic Chemistry, 74(15), 5123–5134. http://doi.org/10.1021/jo900238q	en_US
dc.identifier.uri	http://hdl.handle.net/1808/23638
dc.description.abstract	(E)-5-Nitro-6-(2-hydroxystyryl)pyrimidine-2,4(1H,3H)-dione (9) was identified as a novel inhibitor of Schizosaccharomyces pombe lumazine synthase by high-throughput screening of a 100,000 compound library. The Ki of 9 vs. Mycobacterium tuberculosis lumazine synthase was 95 μM. Compound 9 is a structural analog of the lumazine synthase substrate, 5-amino-6-(D-ribitylamino)-2,4-(1H,3H)pyrimidinedione (1). This indicates that the ribitylamino side chain of the substrate is not essential for binding to the enzyme. Optimization of the enzyme inhibitory activity through systematic structure modification of the lead compound 9 led to (E)-5-nitro-6-(4-nitrostyryl)pyrimidine-2,4(1H,3H)-dione (26), which has a Ki of 3.7 μM vs. M. tuberculosis lumazine synthase.	en_US
dc.publisher	American Chemical Society	en_US
dc.rights	Per SHERPA/RoMEO 4/12/2017: Author's Pre-print: grey tick subject to Restrictions below, author can archive pre-print (ie pre-refereeing) Restrictions: Must obtain written permission from Editor Must not violate ACS ethical Guidelines Author's Post-print: grey tick subject to Restrictions below, author can archive post-print (ie final draft post-refereeing) Restrictions: If mandated by funding agency or employer/ institution If mandated to deposit before 12 months, must obtain waiver from Institution/Funding agency or use AuthorChoice 12 months embargo Publisher's Version/PDF: cross author cannot archive publisher's version/PDF General Conditions: On author's personal website, pre-print servers, institutional website, institutional repositories or subject repositories Non-Commercial Must be accompanied by set statement (see policy) Must link to publisher version Publisher's version/PDF cannot be used	en_US
dc.title	Discovery and Development of a Small Molecule Library with Lumazine Synthase Inhibitory Activity	en_US
dc.type	Article	en_US
kusw.kuauthor	Georg, Gunda
kusw.kuauthor	Ye, Qi-Zhuang
kusw.kudepartment	Medicinal Chemistry	en_US
dc.identifier.doi	10.1021/jo900238q	en_US
kusw.oaversion	Scholarly/refereed, author accepted manuscript	en_US
kusw.oapolicy	This item meets KU Open Access policy criteria.	en_US
dc.rights.accessrights	openAccess

Files in this item

Name:: Georg_2009.pdf
Size:: 1.148Mb
Format:: PDF

View/Open

This item appears in the following Collection(s)

The University of Kansas prohibits discrimination on the basis of race, color, ethnicity, religion, sex, national origin, age, ancestry, disability, status as a veteran, sexual orientation, marital status, parental status, gender identity, gender expression and genetic information in the University’s programs and activities. The following person has been designated to handle inquiries regarding the non-discrimination policies: Director of the Office of Institutional Opportunity and Access, IOA@ku.edu, 1246 W. Campus Road, Room 153A, Lawrence, KS, 66045, (785)864-6414, 711 TTY.