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Nicholas Natale
Professor

Phone: (406) 243-4132

Email: nicholas.natale@umontana.edu

Nicholas R. Natale received his B.S. in Chemistry (1976), and his Ph.D. in Organic Chemistry (1979), at Drexel University in Philadelphia, under the guidance of mentor Professor Robert O. Hutchins. His research focused on synthetic methodology, and his dissertation was entitled "Trilogy of Molecular Transfiguration". He studied the asymmetric synthesis of dihydropyridines as a Postdoctoral Fellow at Colorado State University (1979-81) in the research group of Professor Albert I. Meyers. His first independent academic position was at the University of Idaho, where he rose through the ranks to Professor. He was recipient of the Idaho Academy of Science Distinguished Science Communicator Award in 2004. He was named Professor of Medicinal Chemistry in the Department of Biomedical and Pharmaceutical Sciences, at The University of Montana in 2007.Nick received the 2007 American Chemical Society E. Ann Nalley Northwest Region Award for Volunteer Service. His publications, published abstracts, presentations at scientific meetings, and invited lectures total over 350.

RESEARCH STATEMENT

The Natale lab is interested in the role of chirality and conformational dynamics in bioactive small molecules. Specifically, the group has developed synthetic methodology which is applicable to the development of Structure Activity Relationships (SAR) for a number of isoxazole containing drug candidates.

In the area of antihypertensive agents, bioisosteric replacement of the 4-carbocyclic aryl of 4-aryl-1,4-dihydropyridines in the nifedipine class with isoxazoles results in molecules which retain robust calcium channel antagonist activity. Significantly the 4-isoxazolyl-1,4-dihydropyridines (IDHPs) lack the significant negative ionotropic activity of most nifedipine analogs. Chirality in the isoxazole C-5 position was built using a stoichiometric chiral auxilliary based asymmetric lateral metalation, and the resulting eutomer exhibited 3.7 nanomolar binding to the calcium channel, and a eudismic ratio of 56.7. The unique SAR of the IDHPs has been explained by a sequence homology model of the calcium channel based on MacKinnon's landmark KcsA structure. Currently the group has developed a series of IDHPs covalently linked to fluorophores, and hope to elucidate the important conformational dynamics in the gating of calcium channels.

Molecules prepared in the Natale lab have been evaluated in the National Cancer Institute's (NCI) Developmental Therapeutic Program (DTP), and exhibited promising anticancer activity in both 60 cell line in vitro, and hollow fiber in vivo assays. The role of the isoxazole is to preorganize DNA binding moieties in three dimensions, and the current working hypothesis is that the molecules exert their biological effect by stabilization of G4 DNA. Targeting a unique conformation of DNA is postulated to lead to the switching off of oncogenes capable of forming G4 conformers, and unprecedented selectivity is the potential advantage of this approach.

Finally, using a recently develop catalytic asymmetric synthesis of glutamate analogs, the Natale group has discovered a novel SAR distinction between glutamate receptors and transporters, which may provide useful tools to delineate molecules with enhanced selectivity for neurological disorders.

The synthetic tools developed in the Natale group are potentially applicable to other classes of isoxazole containing pharmaceuticals, and plans for drug discovery efforts for treatment of type 2 diabetes (T2D), and infectious disease are in the works.

KEY PUBLICATIONS
  1. The Catalytic Asymmetric Addition of Alkyl- and Aryl- zinc Reagents to an Isoxazolyl Aldehyde, Jared K. Nelson, Brendan Twamley, Trinidad J. Villalobos, and N.R. Natale, Tetrahedron Lett., 2008, 49, 5957-5960. 

  2. Synthetic Utility of Epoxides for Chiral Functionalization of Isoxazoles, Jared K. Nelson, Christopher T. Burns, Miles P. Smith, Brendan Twamley and N.R. Natale, Tetrahedron Lett., 2008, 49, 3078-82.

  3. Preparation and Crystal Structures of Two 3-Anthracenyl Isoxazolyl Sulfonamides, Chun Li, Brendan Twamley and N.R. Natale,  J. Heterocycl. Chem., 2008, 45, 259-264.

  4. Ethyl 4-(2-bromomethyl-5,5-dimethyl-1,3-dioxan-2-yl)-5-methylisoxazole-3-carboxylate, Brendan Twamley, Monika Szabon-Watola, Shikha Sharma and Nicholas R. Natale, Acta Cryst., 2007, E63, o2258-o2260.

  5. Can Selective Ligands for Glutamate Binding Proteins be Rationally Designed?, N.R. Natale, K. Magnusson, and J.K. Nelson, Current Topics in Medicinal Chemistry, Symposium-in-print, 2006, 6, 823-846.

  6. Ethyl-3-(10-chloroanthracenyl)-5-(1-phenyl-2-hydroxylethylenyl) isoxazole-4-carboxylate: an enol from Dess-Martin oxidation, Chun Li, Brendan Twamley, and N.R.Natale, Acta Cryst., 2006, E62, o854-o856.

  7. Isoxazole Ionotropic Glutamate Neurotransmitters, David J. Burkhart and N.R. Natale, Current Medicinal Chemistry, invited review, 2005, 12, 617-627.

  8. The Catalytic Asymmetric Synthesis of Glutamate Analogues, David J. Burkhart, Andrew R. McKenzie, Jared K. Nelson, Katherine I. Myers, Xue Zhao, Kathy R. Magnusson, and Nicholas R. Natale, Org. Lett., 2004, 6, 1285-8.

  9. Unique Structure Activity Relationship of 4-Isoxazolyl-1,4-dihydropyridines, Gerald Zamponi, Stephanie C. Stotz, Richard J. Staples, Tina A. Rogers, Jared K. Nelson, Victoria Hulubei, Alex Blumenfeld, and N.R. Natale, J. Med. Chem., 2003, 46, 87-96.

  10. The Isoxazole as a linchpin for molecules which target folded DNA conformations: Selective Lateral Lithiation and Palladation, Xiaochun Han, Chun Li, Kevin C. Rider, Alex Blumenfeld, Brendan Twamley, and N.R. Natale, Tetrahedron Lett., 2002, 43, 7673-7677.