Abstract

Diversity-oriented synthesis (DOS) has the potential to empower academic chemists and biologists to explore the relationship between chemistry space and biological activity, leading to major advances in biology and medicine. The Center will perform fundamental research to advance the technology and pathways available for DOS, to help realize its full potential. We will develop a new platform (megabeads) that is optimized for screening by biologists; we will use DOS to discover new catalysts, increasing the range of DOS pathways available; and we will develop several new strategies for library synthesis that explore areas of chemical space that are currently sparsely populated. Two Cores will support the Projects. The Library Synthesis, Formatting and Curation Core will work to automate reaction development, currently the rate-limiting step in DOS, and will make the crucial link to biological screening by providing our libraries to the existing ICCB screening facility in a common format. The Cheminformatics Core will compute molecular descriptors for planned libraries, compare them to a reference set of known molecules, and advise Project researchers on ways to maximize the contribution of a given library to the exploration of chemical space.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
3P50GM069721-02S1
Application #
6951015
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Schwab, John M
Project Start
2003-09-30
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$74,999
Indirect Cost

  Institution

Name
Harvard University
Department
Chemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Wawer, Mathias J; Jaramillo, David E; Dan?ík, Vlado et al. (2014) Automated Structure-Activity Relationship Mining: Connecting Chemical Structure to Biological Profiles. J Biomol Screen 19:738-48
Gerard, Baudouin; O'Shea, Morgan Welzel; Donckele, Etienne et al. (2014) Correction to Application of a Catalytic Asymmetric Povarov Reaction using Chiral Ureas to the Synthesis of a Tetrahydroquinoline Library. ACS Comb Sci 16:46
Bergonzini, Giulia; Schindler, Corinna S; Wallentin, Carl-Johan et al. (2014) Photoredox Activation and Anion Binding Catalysis in the Dual Catalytic Enantioselective Synthesis of ?-Amino Esters. Chem Sci 5:
Wawer, Mathias J; Li, Kejie; Gustafsdottir, Sigrun M et al. (2014) Toward performance-diverse small-molecule libraries for cell-based phenotypic screening using multiplexed high-dimensional profiling. Proc Natl Acad Sci U S A 111:10911-6
Over, Björn; McCarren, Patrick; Artursson, Per et al. (2014) Impact of stereospecific intramolecular hydrogen bonding on cell permeability and physicochemical properties. J Med Chem 57:2746-54
Xu, Hao; Zhang, Hu; Jacobsen, Eric N (2014) Chiral sulfinamidourea and strong Brønsted acid-cocatalyzed enantioselective Povarov reaction to access tetrahydroquinolines. Nat Protoc 9:1860-6
Frumm, Stacey M; Fan, Zi Peng; Ross, Kenneth N et al. (2013) Selective HDAC1/HDAC2 inhibitors induce neuroblastoma differentiation. Chem Biol 20:713-25
Rajapaksa, Naomi S; McGowan, Meredeth A; Rienzo, Matthew et al. (2013) Enantioselective total synthesis of (+)-reserpine. Org Lett 15:706-9
Wang, Yikai; Jimenez, Miguel; Sheehan, Patrick et al. (2013) Selective access to trisubstituted macrocyclic E- and Z-alkenes from the ring-closing metathesis of vinylsiloxanes. Org Lett 15:1218-21
Lalonde, Mathieu P; McGowan, Meredeth A; Rajapaksa, Naomi S et al. (2013) Enantioselective formal aza-Diels-Alder reactions of enones with cyclic imines catalyzed by primary aminothioureas. J Am Chem Soc 135:1891-4

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