The goal of this application is to design and construct pilot scale libraries comprised of novel heterocycles with an emphasis on skeletal, stereochemical and peripheral functional group (FG) diversity. In particular, we will focus our initial efforts on libraries comprised of sulfur and phosphorus-containing small molecules and analogues thereof, we term generally as S- and P-heterocycles.
We aim to design and construct the following libraries using a """"""""linchpin to scaffolds to library"""""""" paradigm where a combination of linchpin design, reaction manifolds and in silico diversity screening (PubChem) will guide our efforts in mining unique chemical space in a dynamic manner. Integration of an array of facilitated synthetic protocols utilizing immobilized reagents and technologies developed in our laboratory will enable pilot-scale libraries construction. High-throughput purification via mass-directed fractionation will be used in all cases to verify compound purity and identity. The libraries synthesized will comprise of individual sublibraries of ~40-100 compounds per linchpin in sufficient quantities (10-15 mg) and high purity (>90%) for HTS on numerous platforms within the MLSCN. We are projecting delivery of 750 compounds per year. Ultimately, these libraries will be evaluated via the Molecular Library Screening Network (MLSCN) in order to uncover lead structures for further development. We are well positioned to meet this goal by employing methodologies developed in our laboratories that focus on scaffolds that are designed according to medicinal chemistry principles, and use efficient scaffold generation/diversification strategies and facilitated synthetic protocols for library production. Overall, this platform will enable us to produce scalable, diverse libraries based on multiple novel scaffolds and allow us to probe both biological and chemical space in a dynamic manner.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Biotechnology Resource Grants (P41)
Project #
5P41GM076302-06
Application #
7882659
Study Section
Special Emphasis Panel (ZRG1-BCMB-R (50))
Program Officer
Lees, Robert G
Project Start
2005-09-23
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2013-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$367,150
Indirect Cost
Name
University of Kansas Lawrence
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Loh, Joanna K; Asad, Naeem; Samarakoon, Thiwanka B et al. (2015) Modular, One-Pot, Sequential Aziridine Ring Opening-S(N)Ar Strategy to 7-, 10-, and 11-Membered Benzo-Fused Sultams. J Org Chem 80:9926-41
Asad, Naeem; Samarakoon, Thiwanka B; Zang, Qin et al. (2014) Rapid, scalable assembly of stereochemically rich, mono- and bicyclic acyl sultams. Org Lett 16:82-5
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
Boodram, Sherry N; McCann, Lucas C; Organ, Michael G et al. (2013) Quantitative affinity electrophoresis of RNA-small molecule interactions by cross-linking the ligand to acrylamide. Anal Biochem 442:231-6
Ullah, Farman; Zang, Qin; Javed, Salim et al. (2012) Synthesis of an Isoindoline-Annulated, Tricyclic Sultam Library via Microwave-Assisted, Continuous-Flow Organic Synthesis (MACOS). Synthesis (Stuttg) 44:
Faisal, Saqib; Ullah, Farman; Maity, Pradip K et al. (2012) Facile (triazolyl)methylation of MACOS-derived benzofused sultams utilizing ROMP-derived OTP reagents. ACS Comb Sci 14:268-72
Zang, Qin; Javed, Salim; Porubsky, Patrick et al. (2012) Synthesis of a unique isoindoline/tetrahydroisoquinoline-based tricyclic sultam library utilizing a Heck-aza-Michael strategy. ACS Comb Sci 14:211-7
Zang, Qin; Javed, Salim; Hill, David et al. (2012) Automated synthesis of a library of triazolated 1,2,5-thiadiazepane 1,1-dioxides via a double aza-Michael strategy. ACS Comb Sci 14:456-9
Loh, Joanna K; Yoon, Sun Young; Samarakoon, Thiwanka B et al. (2012) Exploring chemical diversity via a modular reaction pairing strategy. Beilstein J Org Chem 8:1293-302
Ullah, Farman; Zang, Qin; Javed, Salim et al. (2012) Multicapillary Flow Reactor: Synthesis of 1,2,5-Thiadiazepane 1,1-Dioxide Library Utilizing One-Pot Elimination and Inter-/Intramolecular Double aza-Michael Addition Via Microwave-Assisted, Continuous-Flow Organic Synthesis (MACOS). J Flow Chem 2:

Showing the most recent 10 out of 40 publications