Highly diverse compound libraries consisting of under-explored chemotypes will be provided to the NIH for screening in the NIH Molecular Library Screening Center Network (MLSCN). The central hypothesis of this application is that compound libraries, which contain novel chemotypes, incorporate privileged structures, and cover largely unexplored diversity space, will provide new tools to study the functions of genes, signaling pathways, and other complex biological systems. The libraries incorporate activity-enhancing features such as privileged structures and others, known to be important for interactions with macromolecular structures. The libraries are therefore expected to have high hit rates in biological assays. The libraries have been designed to provide diverse chemotypes as judged by their diversity scores. The diversity scores were derived from analysis against the NIH PubChem database and demonstrate that the proposed scaffolds populate sparsely populated diversity space. Only compounds from sparsely and moderately populated chemical space possessing adequate solubility will be selected for synthesis in this project. Five subprojects are proposed that offer varied chemotypes: (1) Synthesis of libraries with nitrogen-containing cyclic scaffolds; (2) Design and synthesis of factorial libraries from privileged structures; (3) Novel medium-ring size combinatorial libraries; (4) Diversity-oriented library synthesis; (5) Natural product-derived libraries. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Biotechnology Resource Grants (P41)
Project #
1P41GM081267-01
Application #
7291334
Study Section
Special Emphasis Panel (ZGM1-PPBC-3 (PL))
Program Officer
Schwab, John M
Project Start
2007-09-01
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$452,362
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Gu, Xingxian; Georg, Gunda I (2015) Regioselective C5-alkylation and C5-methylcarbamate formation of 2,3-dihydro-4-pyridones and C3-alkylation and C3-methylcarbamate formation of 4-(pyrrolidin-1-yl)furan-2(5H)-one. Tetrahedron Lett 56:5874-5877
Seki, Hajime; Georg, Gunda I (2014) Enantiospecific Synthesis and Biological Investigations of a Nuphar Alkaloid: Proposed Structure of a Castoreum Component. European J Org Chem 2014:3777-3783
Yu, Yi-Yun; Georg, Gunda I (2014) Biomimetic Aerobic C-H Olefination of Cyclic Enaminones at Room Temperature: Development toward the Synthesis of 1,3,5-Trisubstituted Benzenes. Adv Synth Catal 356:1359-1369
Kim, Yong Wook; Georg, Gunda I (2014) Boron-Heck reaction of cyclic enaminones: regioselective direct arylation via oxidative palladium(II) catalysis. Org Lett 16:1574-7
Ranade, Adwait R; Georg, Gunda I (2014) Enantioselective synthesis of 3,4-dihydro-1,2-oxazepin-5(2H)-ones and 2,3-dihydropyridin-4(1H)-ones from ?-substituted ?-hydroxyaminoaldehydes. J Org Chem 79:984-92
Hutt, Oliver E; Doan, Trinh L; Georg, Gunda I (2013) Synthesis of skeletally diverse and stereochemically complex library templates derived from isosteviol and steviol. Org Lett 15:1602-5
Yu, Yi-Yun; Bi, Lei; Georg, Gunda I (2013) Palladium-catalyzed direct C-H arylation of cyclic enaminones with aryl iodides. J Org Chem 78:6163-9
Yu, Yi-Yun; Georg, Gunda I (2013) Dehydrogenative alkenylation of uracils via palladium-catalyzed regioselective C-H activation. Chem Commun (Camb) 49:3694-6
Kim, Yong Wook; Niphakis, Micah J; Georg, Gunda I (2012) Copper-assisted palladium(II)-catalyzed direct arylation of cyclic enaminones with arylboronic acids. J Org Chem 77:9496-503
Pepe, Antonella; Pamment, Michael; Georg, Gunda I et al. (2011) Synthesis of fused bicyclic systems with nitrogen atom at the bridgehead, including indolizidines and quinolizidines. J Org Chem 76:3527-30

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