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Gary A. Sulikowski

Title and Contact Information

Stevenson Professor of Chemistry

Office: 12415-F MRB IV
Phone: (615) 343-4155
EmailWebsite

Education

Ph.D., University of Pennsylvania, 1989

Specialties

VICB
Organic Chemistry
Natural Products
Medicinal Chemistry
Chemical Biology
Biosynthesis
Bioorganic Chemistry
Biochemistry

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Sulikowski

Research

Natural product total synthesis. We have maintained a longstanding interest in the development of synthetic strategies leading to the total synthesis of complex natural products. Historically, natural products present opportunities to address defined synthetic challenges presented in the novel structure of a natural product target. Currently we are pursuing the total synthesis of marine diterpenes (bielschowskysin) and alkylpiperidine alkaloids (upenamide and xestocyclamine A). These studies also serve as an excellent opportunity for the training of young scientists interested in the art and practice of chemical synthesis. Increasingly our motivation in the area of total synthesis is the biological study of synthetic products and derivatives (arachidonic acid metabolites and antimicrobial natural products).

Biology and chemistry of natural products. Natural products are among the most structurally complex and privileged of the bioactive small molecules. Analysis of the sources of small molecule drugs approved between 1981 and 2006 indicates that over half of the new chemical entities declared in this timeframe were natural products or derived from natural products. However, from the perspective of medicinal chemistry, the complex molecular architecture of natural products continues to pose a significant challenge to access not only quantities of the parent structure but also analogs to establish structure-activity relationships (SAR). In addition to utilizing our skills in chemical synthesis to access and modify natural products we also attempt to harness the biosynthetic machinery to access complex natural products, sometimes in collaboration with groups with expertise the genetic modification of biosynthetic pathways. We were the first group to identify the biosynthesis of the complex nonadrides CP-225,917 and CP-263,114 and study the development of this biosynthetic dimerization in the lab. More recently, working with the Bachmann group we have developed fluorescent derivatives the cell selective cytotoxic agent apoptolidin and demonstrated its localization in the mitochondria. We are also one of two groups in the world that developed a chemical synthesis of the microbial thiol bacillithiol, now being used by investigators worldwide.

Chemical probes and pre-clinical lead development. Phenotypic and functional screens of compound libraries are currently being used by a variety of biomedical investigators in Cell and Developmental Biology, Microbiology and Immunology and Pharmacology. We provide chemistry support in lead development and target identification studies. In some cases we have optimized lead potency and metabolic compound properties allowing animal studies to provide preliminary validation of new targets for therapeutic development.

 

Selected Publications

Williams CH,  Hempel JE,  Hao J,  Frist AY,  Williams MM,  Fleming JT ,  Sulikowski GA,  Cooper MK,  Chiang C,  Hong CC An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition. Cell Reports.   2015, 11(1):43-50. 

DeGuire SM, Earl DC, Du Y, Crews BA, Jacobs AT, Ustione A, Daniel C, Chong KM, Marnett LJ, Piston DW, Bachmann BO, Sulikowski GA. Fluorescent probes of the apoptolidins and their utility in cellular localization studies. Angewandte Chemistry International Ed in English. 2015, 54(3):961-4.

Evans SM, Kim K, Moore CE, Uddin MI, Capozzi ME, Craft JR, Sulikowski GA, Jayagopal A. Molecular probes for imaging of hypoxia in the retina. Bioconjugate Chemistry. 2014, 25(11):2030-7.

Romaine IM, Taylor RW, Saidu SP, Kim K, Sulikowski GA, Zwiebel LJ, Waterson AG.Narrow SAR in odorant sensing Orco receptor agonists. Bioorganic & Medicinal Chemistry Letters. 2014, 24(12):2613-6.

Mike LA, Choby JE, Brinkman PR, Olive LQ, Dutter BF, Ivan SJ, Gibbs CM, Sulikowski GA, Stauff DL, Skaar EP. Two-component system cross-regulation integrates Bacillus anthracis response to heme and cell envelope stress. PLoS Pathogens. 2014, 10(3):e1004044.

Wen, W.D.; Wu, W.J.; Romaine, I.M.; Kaufmann, K.; Du, Y.; Sulikowski, G.A.; Weaver, C.D.; Lindsley, C.W. Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors. Bioorganic & Medicinal Chemistry Letters. 2013, 23 (16): 4562-4566.

Mike, L.A.; Dutter, B.F.; Stauff, D.L.; Moore, J.L.; Vitko, N.P.; Aranmolate, O.; Kehl-Fie, T.E.; Sullivan, S.; Reid, P.R.; DuBois, J.L.; Richardson, A.R.; Caprioli, R.M.; Sulikowski, G.A.; Skaar, E.P. Activation of heme biosynthesis by a small molecule that is toxic to fermenting Staphylococcus aureus. Proceedings of The National Academy of Sciences of The United States of America. 2013, 110 (20): 8206-8211.

Kaufmann, K.; Romaine, I.; Days, E.; Pascual, C.; Malik, A.; Yang, L.Y.; Zou, B.D.; Du, Y.; Sliwoski, G.; Morrison, R.D.; Denton, J.; Niswender, C.M.; Daniels, J.S.; Sulikowski, G.A.; Xie, X.M.; Lindsley, C.W.; Weaver, C.D. ML297 (VU0456810), the First Potent and Selective Activator of the GIRK Potassium Channel, Displays Antiepileptic Properties in Mice. ACS Chemical Neuroscience. 2013, 4 (9): 1278-1286.

Thompson, M.K.; Keithly, M.E.; Harp, J.; Cook, P.D.; Jagessar, K.L.; Sulikowski, G.A.; Armstrong, R.N. Structural and Chemical Aspects of Resistance to the Antibiotic Fosfomycin Conferred by FosB from Bacillus cereus. Biochemistry. 2013, 52 (41): 7350-7362.

Ramos-Hunter, S.J.; Engers, D.W.; Kaufmann, K.; Du, Y.; Lindsley, C.W.; Weaver, C.D.; Sulikowski, G.A. Discovery and SAR of a novel series of GIRK1/2 and GIRK1/4 activators. Bioorganic & Medicinal Chemistry Letters. 2013, 23 (18): 5195-5198.

Mike, L.A.; Dutter, B.F.; Stauff, D.L.; Moore, J.L.; Vitko, N.P.; Aranmolate, O.; Kehl-Fie, T.E.; Sullivan, S.; Reid, P.R.; DuBois, J.L.; Richardson, A.R.;Caprioli, R.M.; Sulikowski, G.A.; Skaar, E.P. Activation of heme biosynthesis by a small molecule that is toxic to fermenting Staphylococcus aureus. Proceedings of The National Academy of Sciences of The United States of America. 2013, 110 (20): 8206-8211.

Taylor, R.W.; Romaine, I.M.; Liu, C.; Murthi, P.; Jones, P.L.; Waterson, A.G.; Sulikowski, G.A.; Zwiebel, L.J. Structure-Activity Relationship of a Broad-Spectrum Insect Odorant Receptor Agonist. ACS Chemical Biology. 2012, 7 (10): 1647-1652.

Baranczak, A.; Sulikowski, G.A. Cascade assembly of the benz[a]anthraquinone ring system common to the angucycline antibiotics. Tetrahedron Letters. 2012, 53 (11): 1345-1346.

Baranczak, A.; Sulikowski, G.A. Synthetic Studies Directed toward Dideoxy Lomaiviticinone Lead to Unexpected 1,2-Oxazepine and Isoxazole Formation. Organic Letters. 2012, 14 (4): 1027-1029.

Melancon, B.J.; Lamers, A.P.; Bridges, T.M.; Sulikowski, G.A.; Utley, T.J.; Sheffler, D.J.; Noetzel, M.J.; Morrison, R.D.; Daniels, J.S.; Niswender, C.M.; Jones, C.K.; Conn, P.J.; Lindsley, C.W.; Wood, M.R. Development of a more highly selective M-1 antagonist from the continued optimization of the MLPCN Probe ML012. Bioorganic & Medicinal Chemistry Letters. 2012, 22 (2): 1044-1048.

DeGuire, S.M.; Ma, S.T; Sulikowski, G.A. Synthesis of a Bicyclobutane Fatty Acid Identified from the Cyanobacterium Anabaena PCC 7120. Angewandte Chemie-Internationa Edition. 2011, 50 (42): 9940-9942.

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