The overall goal of this Center of Excellence in Chemical Methodologies and Library Development grant application is to generate novel chemical libraries based on original research carried out in the areas of synthesis and analysis of novel peptide mimetics (Project 1), the combination of innovative methods for diversity-oriented synthesis and strategic separations (Project 2), and the development and implementation of fluoropolymer-based microreactors (Project 3). Our Program will develop new separation technologies using fluorous phase synthesis strategies, design and develop microreactors for nano-scale highly parallel organic synthesis, and discover new chiral stationary phases for liquid phase chromatography. Each Project has two stages: research and application. At the research stage, new methodologies will be developed in individual research groups. At the development stage, a centralized facility, the Diversity-Oriented Synthesis (DOS) Core with convenient access to state-of-the-art automated synthesis, separation, and analysis equipment, will validate the protocols and scale-up library synthesis to access 500-10,000 single compounds per library. This arrangement will provide truly independent validation for all new methodologies and provide the Projects with immediate """"""""real world"""""""" feedback of utility and practicality. Rigorous quality control will ensure high purity samples that will be shared with collaborators in the biological fields. This Compound Library, envisioned to be composed of ultimately >50,000 structurally diverse samples in 10-20 mg quantities, will also be accessible to outside parties from industry and academe. While academic labs have developed many new methods for library synthesis and contributed important insights toward efficient automation for library production and analysis, they have fallen short in actually producing libraries and making them accessible to non-specialized labs. Our Center Program will address this deficiency and realize a new paradigm in research validation and library scale-up. It combines the power of academic research and creativity in Chemistry with cutting-edge tools of automation in synthesis, analysis, and separation in an integrated, interdisciplinary manner that includes microscale device development and biological screening. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
3P50GM067082-03S1
Application #
6949825
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Schwab, John M
Project Start
2002-09-30
Project End
2007-08-31
Budget Start
2004-09-30
Budget End
2005-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$74,947
Indirect Cost
Name
University of Pittsburgh
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Saydmohammed, Manush; Vollmer, Laura L; Onuoha, Ezenwa O et al. (2018) A High-Content Screen Reveals New Small-Molecule Enhancers of Ras/Mapk Signaling as Probes for Zebrafish Heart Development. Molecules 23:
Wissel, Gloria; Deng, Feng; Kudryavtsev, Pavel et al. (2017) A structure-activity relationship study of ABCC2 inhibitors. Eur J Pharm Sci 103:60-69
Gleixner, Amanda M; Hutchison, Daniel F; Sannino, Sara et al. (2017) N-Acetyl-l-Cysteine Protects Astrocytes against Proteotoxicity without Recourse to Glutathione. Mol Pharmacol 92:564-575
Brand, Rhonda M; Epperly, Michael W; Stottlemyer, J Mark et al. (2017) A Topical Mitochondria-Targeted Redox-Cycling Nitroxide Mitigates Oxidative Stress-Induced Skin Damage. J Invest Dermatol 137:576-586
McCabe, Stephanie R; Wipf, Peter (2017) Eight-Step Enantioselective Total Synthesis of (-)-Cycloclavine. Angew Chem Int Ed Engl 56:324-327
Manos-Turvey, Alexandra; Al-Ashtal, Hiba A; Needham, Patrick G et al. (2016) Dihydropyrimidinones and -thiones with improved activity against human polyomavirus family members. Bioorg Med Chem Lett 26:5087-5091
Brummond, Kay M; Kocsis, Laura S (2015) Intramolecular didehydro-Diels-Alder reaction and its impact on the structure-function properties of environmentally sensitive fluorophores. Acc Chem Res 48:2320-9
Rupakheti, Chetan; Virshup, Aaron; Yang, Weitao et al. (2015) Strategy to discover diverse optimal molecules in the small molecule universe. J Chem Inf Model 55:529-37
Ma, Jing; Lim, Chaemin; Sacher, Joshua R et al. (2015) Mitochondrial targeted ?-lapachone induces mitochondrial dysfunction and catastrophic vacuolization in cancer cells. Bioorg Med Chem Lett 25:4828-33
Wissel, Gloria; Kudryavtsev, Pavel; Ghemtio, Leo et al. (2015) Exploring the structure-activity relationships of ABCC2 modulators using a screening approach. Bioorg Med Chem 23:3513-25

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