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Name: Nicholas Natale

Title: Professor


Phone: 406-243-4132

Office: SB 477B

Lab Phone: 406-243-4125

Lab: SB 471



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. Nick gratefully accepted the Mershon Award of the Montana Academy of Science in 2011. Forty students in the Natale group have won 85 awards for their research presentations or teaching. The Natale group alumni count among their number a company president, three pharma group leaders, and eleven who have taught at the college level, including two full professors.


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.



"Novel Di-aryl-substituted Isoxazoles act as noncompetitive inhibitors of the Xc- Glutamate Cystine exchanger", J. Newell, C.M. Keyari, P. Diaz, N.R. Natale, S. Patel, R. Bridges, Neurochem. International, 2014,73, 132-138. PMID: 24333322.

"Diethyl 4-(biphenyl-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate", Scott A. Steiger, Anthony J. Monacelli, Chun Li, Janet L. Hunting and N. R. Natale, Acta Cryst.,2014,E70o791-o792. doi:10.1107/S1600536814013294.

"4-Isoxazolyl-1,4-dihydropyridines: a tale of two scaffolds", Natale, N.R. and Steiger, S.A. Future Med. Chem., 2014, 6(8),923-943. PMID: 24962283.

"The effect of bromine scanning around the phenyl group of 4-phenyl-hexahydroquinolone derivatives", Scott A. Steiger, Anthony J. Monacelli, Chun Li, Janet L. Hunting, N.R. Natale, Acta Cryst., 2014, C70, 790-795. doi:10.1107/S2053229614015617.

Nathan S. Duncan, Howard D. Beall, Alison K. Kearns, Chun Li and Nicholas R. Natale. Ethyl 3-(9'-chloro-10'-oxo-9',10'-dihydroanthracen-9'-yl)-5-methylisoxazole-4-carboxylateActa Cryst, 2014,E70, o315-o316.

Monika I. Szabon-Watola, Sarah Ulatowski, Kathleen M. George, Christina D. Hayes, Scott A. Steiger, and N.R. Natale, Fluorescent probes of the Isoxazole-Dihydropyridine Scaffold: MDR-1 Binding and homology model. Bioorg.Med. Chem. Lett., 2014, 24(1), 117-121.

Chun Li, Michael J. Campbell, Matthew J. Weaver, Nathan S. Duncan, Janet L. Hunting and Nicholas R. Natale, Ethyl 3-(10-bromo-anthracen-9--yl)-5-methyl-1,2-oxazole-4-carboxylateActa Cryst 2013,E69, o1804-o1805.

Afnan A. (Lilly)  Matti, Joseph Mirzaei, John Rudolph, Stephen A. Smith, Jayme Newell, Sarjubhai A. Patel, Michael Braden, Richard J. Bridges, and Nicholas R. Natale,Microwave accelerated synthesis of Isoxazole inhibitors of the System xc- transporter: initial homology model. Bioorg. Med. Chem. Lett., 2013, 23, 5931-5935. PMID: 24042010.

Campana,C.; Mirzaei, J.; Koerner, C.; Gates, C.; NataleN.R. 3-(1,3-Diphenylpropan-2-yl)-4-methyl-6-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one. Acta Cryst., 2013, E69, o1680-o1681.

Victoria Hulubei, Scott B. Meikrantz,  David A. Quincy, Tina Houle, John I. McKenna, Mark E. Rogers, Scott Steiger, N.R.Natale, 4-Isoxazolyl-1,4-dihydropyridines exhibit binding at the multidrug resistance transporter.Bioorg. Med. Chem., 2012, 20, 6613-6620. Pubmed Central NIHMS410433.

Yousef R. Mirzaei, Matthew J. Weaver, Scott A. Steiger, Alison K. Kearns, Mariusz P. Gajewski, Kevin C. Rider, Howard D. Beall, and N.R. NataleImproved synthesis of 3-aryl isoxazoles containing fused aromatic ringsTetrahedron,201268, 10360-10364.  Pubmed Central NIHMS410467.

Richard J. Bridges, N.R. NataleSarjubhai A. Patel, System xc- Glutamate/Cystine Antiporter: An Update on Molecular Pharmacology and Roles Within the CNS. British J. Pharmacol., 2012, 165, 20-34.

Steven W. McDaniel, Charles M. Keyari, Kevin C. Rider, Nicholas R. Natale and Philippe Diaz, "Suzuki-Miyaura Cross-Coupling of Benzylic Bromides Under Microwave Conditions", Tetrahedron Lett., 2011, 52, 5656-5658.

Kevin C. Rider, David J. Burkhart, Chun Li, Andrew R. McKenzie, Jared K. Nelson, and Nicholas R. NatalePreparation of chiral isoxazole carbinols via catalytic asymmetric Corey-Bakshi-Shibata reductionARKIVOC, 2010, part (viii), pages 97-107. Commemorative issue in honor of Drs. Bruce E. and Cynthia A. Maryanoff.

Patel S.A, Rajale T., O'Brien E., Burkhart D.J., Nelson J.K., Twamley B., Blumenfeld A., Szabon-Watola M.I., Gerdes J.M., Bridges R.J., and Natale N.R. Isoxazole analogues Bind the System xc- Transporter: Structure-activity Relationship and Pharmacophore ModelBioorg. Med. Chem., 2010, 18, 202-213.

Gajewski M.P., Beall H.D., Schnieder M., Stranahan S.M., Mosher M.D., Rider K.C., and Natale N.R. Bis-Anthracenyl Isoxazolyl Amides have Enhanced Anticancer Activity.Bioorg. Med. ChemLett. 2009, 19, 4067-4069. doi: 10.1016/j.bmcl.2009.06.019.

Han X., Li C., Mosher M.D., Rider K.C., Zhou P., Crawford R.L., Fusco W., Paszczynski A., and Natale N.R. Design, Synthesis and Biological Evaluation of A Novel Class of Anticancer Agents: Anthracenylisoxazole Lexitropsin ConjugatesBioorg. Med. Chem., 2009, 17, 1671-1680.

Natale N.R., Szabon-Watola M.I., Twamley B., Bridges R.J., Patel S., and Rajale T. Ethyl 4-{1-[(2,4-Dinitro-phenyl)-hydrazono]-ethyl}-5-(naphthalen-2-ylmethoxymethyl)-isoxazole-3-carboxylate”, Acta Cryst., 2009, E65o144-o145.

Nelson J.K., Twamley B., Villalobos T.J., and Natale N.R. The Catalytic Asymmetric Addition of Alkyl- and Aryl- zinc Reagents to an Isoxazolyl Aldehyde, Tetrahedron Lett., 2008, 49, 5957-5960.

Nelson J.K., Burns C.T., Smith M.P., Twamley B., and Natale N.R. Synthetic Utility of Epoxides for Chiral Functionalization of Isoxazoles, Tetrahedron Lett., 2008, 49, 3078-82.

Li C., Twamley B., and Natale N.R. Preparation and Crystal Structures of Two 3-Anthracenyl Isoxazolyl Sulfonamides, J. HeterocyclChem., 2008, 45, 259-264.

Twamley B., Szabon-Watola M., Sharma S., and Natale N.R. Ethyl 4-(2-bromomethyl-5,5-dimethyl-1,3-dioxan-2-yl)-5-methylisoxazole-3-carboxylateActa Cryst., 2007, E63o2258-o2260.

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

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

Burkhart D.J., McKenzie A.R., Nelson J.K., Myers K.I., Zhao X., Magnusson K.R., and Natale N.R. The Catalytic Asymmetric Synthesis of Glutamate Analogues, Org. Lett., 2004, 6, 1285-8.

Zamponi G., Stotz S.C., Staples R.J., Rogers T.A., Nelson J.K., Hulubei V., Blumenfeld A., and Natale N.R. Unique Structure Activity Relationship of 4-Isoxazolyl-1,4-dihydropyridines, J. Med. Chem., 2003, 46, 87-96.

The University of Montana-Missoula
The Department of Biomedical & Pharmaceutical Sciences
32 Campus Drive, Skaggs 395
Missoula, MT 59812-1552
Phone 406.243.4767 Fax: 406.243.5228

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