This Pilot Scale Library (PSL) proposal describes the construction of libraries containing novel structures and their submission to the NIH Molecular Libraries Small Molecule Repository (MLSMR). Projects are chosen to maximize (1) the novelty of the submitted structures, as determined by examination of the PubChem database and through an in-house diversity analysis, (2) the likelihood that the libraries proposed will be useful in screening by designing them in analogy with known bioactive agents, and (3) efficiency, by designing syntheses based on established methods for scaffold preparation (generally invented in the Pi's laboratory) combined with straightforward diversification schemes. Once assembled, libraries will be purified using mass directed fractionation techniques and submitted to the Molecular Libraries Small Molecule Repository. The libraries are organized in five major themes. They are (1) alkaloid-like libraries derived from Lewis acid promoted reactions of alkyl azides that afford complex ketones that are subsequently converted to carbamates, amines, indoles, or other heterocyclic products, (2) libraries based on a recently reported class of twisted lactams, (3) libraries inspired by synthetic routes toward marine alkaloids of the cylindricine/lepadiformine class, (4) haouamine A analogs, and (5) libraries inspired by the natural product martinelline and consensus structures of nuclear hormone receptors.

Public Health Relevance

The goal of this Pilot Scale Library proposal is to generate high-quality collections of novel chemical compounds with properties consistent with biological activity. Following submission of these compounds to the Molecular Libraries Small Molecule Repository, they will be screened in numerous assays relevant to human health. Compounds found to be active in these screens can lead to probes that will enhance biomedical research.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Biotechnology Resource Grants (P41)
Project #
5P41GM089164-03
Application #
8290419
Study Section
Special Emphasis Panel (ZRG1-BCMB-U (50))
Program Officer
Lees, Robert G
Project Start
2010-08-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$363,866
Indirect Cost
$116,338
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
McLeod, Michael C; Singh, Gurpreet; Plampin 3rd, James N et al. (2014) Probing chemical space with alkaloid-inspired libraries. Nat Chem 6:133-40
Vekariya, Rakesh H; Liu, Ruzhang; Aubé, Jeffrey (2014) A concomitant allylic azide rearrangement/intramolecular azide-alkyne cycloaddition sequence. Org Lett 16:1844-7
Singh, Gurpreet; Meyer, Angelica; Aubé, Jeffrey (2014) Stereodivergent synthesis of enantioenriched 4-hydroxy-2-cyclopentenones. J Org Chem 79:452-8