The Synthesis Core provides vital enabling technology for the Cystic Fibrosis Research and Translational Core Center. The Synthesis Core (Core D) has all of the equipment required for this effort and Prof. Kurth, the director of the Synthesis Core, has broad experience managing and implementing this equipment in targeted and library small molecule synthesis. The Synthesis Core interacts with Projects in the research base, providing three levels of service. Level I - the highest level of Synthesis Core service - constitutes concentrated involvement by the Synthesis Core in lead optimization and exploration of structure-activity relationships (SAR) by exhaustive synthesis. We anticipate that this level of involvement will continue for AF508-CFTR correctors / potentiators as well as for CaCC/TMEM16A activators. Depending on High- Throughput Screening (HTS) Core (Core A) discovery progress as well as the importance of focused chemistry in meeting Program goals, this level of involvement may also be warranted for other Projects. Level ll - the second level of Synthesis Core involvement - involves the resynthesis of lead compounds, provision of medicinal chemistry advice, and SAR analysis. Many Projects will benefit from this level of Synthesis Core service. Level 111 - the third level of service - requires minimal Synthesis Core effort and consists of providing compounds that have already been synthesized for Project studies as well as providing advice on the medicinal chemistry of active compounds. While individual Project needs will drive most of the Synthesis Core's activities, the Core will also interact with Cores A/B/C/E - primarily in providing any individual compounds needed for their work. The Synthesis Core will interact closely with the HTS Core to verify the identity of hits and validate hit activity by hit re-synthesis and spectroscopic characterization. All lead compounds supplied by the Synthesis Core for Project and Core activities will be highly purified (generally at -95%).

Public Health Relevance

(Instructions): The Synthesis Core provides vital enabling technology for the Cystic Fibrosis Research and Translational Core Center by providing three levels of service. Level I exhaustive synthesis applied to lead optimization and exploration of SAR. Level ll involves resynthesis of lead compounds, medchem advice, and SAR analysis. Level 111 consists of providing known compounds as well as medchem advice

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Center Core Grants (P30)
Project #
5P30DK072517-08
Application #
8564921
Study Section
Special Emphasis Panel (ZDK1-GRB-W (M2))
Project Start
2012-06-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$160,641
Indirect Cost
$48,922
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Piechowicz, Katarzyna A; Truong, Eric C; Javed, Kashif M et al. (2016) Synthesis and evaluation of 5,6-disubstituted thiopyrimidine aryl aminothiazoles as inhibitors of the calcium-activated chloride channel TMEM16A/Ano1. J Enzyme Inhib Med Chem 31:1362-8
Bonser, Luke R; Zlock, Lorna; Finkbeiner, Walter et al. (2016) Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma. J Clin Invest 126:2367-71
Haggie, Peter M; Phuan, Puay-Wah; Tan, Joseph-Anthony et al. (2016) Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis. FASEB J 30:2187-97
Suzuki, Shingo; Sargent, R Geoffrey; Illek, Beate et al. (2016) TALENs Facilitate Single-step Seamless SDF Correction of F508del CFTR in Airway Epithelial Submucosal Gland Cell-derived CF-iPSCs. Mol Ther Nucleic Acids 5:e273
Flores, Alyssa M; Casey, Scott D; Felix, Christian M et al. (2016) Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease. FASEB J 30:1789-97
Cil, Onur; Haggie, Peter M; Phuan, Puay-Wah et al. (2016) Small-Molecule Inhibitors of Pendrin Potentiate the Diuretic Action of Furosemide. J Am Soc Nephrol 27:3706-3714
Jin, Byung-Ju; Smith, Alex J; Verkman, Alan S (2016) Spatial model of convective solute transport in brain extracellular space does not support a "glymphatic" mechanism. J Gen Physiol 148:489-501
Cil, Onur; Phuan, Puay-Wah; Lee, Sujin et al. (2016) CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation. Cell Mol Gastroenterol Hepatol 2:317-327
Esteva-Font, Cristina; Jin, Byung-Ju; Lee, Sujin et al. (2016) Experimental Evaluation of Proposed Small-Molecule Inhibitors of Water Channel Aquaporin-1. Mol Pharmacol 89:686-93
Walentek, Peter; Quigley, Ian K; Sun, Dingyuan I et al. (2016) Ciliary transcription factors and miRNAs precisely regulate Cp110 levels required for ciliary adhesions and ciliogenesis. Elife 5:

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