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Nick Natale

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Personal Summary

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 500.

Research Interests

The Natale lab is interested in the role of chirality and conformational dynamics in bioactive small molecules.  Projects are directed towards medicinal chemistry applications in the realm of multi-drug resistance, antitumor agents and neurotransmitter analogs, all have involved the principles of hypothesis-driven structure-based drug design. The strong tradition of collaborative research that links the development of novel chemical entities by medicinal and synthetic chemists with their novel application to relevant problems in pharmacology was the primary driving force for the relocation of my lab to University of Montana (UM) eight years ago. Recently, I spent a sabbatical at the Anschutz Medical campus at the University of Colorado working with Dr. Don Backos, the Director of their Computational Chemistry and Biology core facility, developing both protein and oligonucleotide models using the Discovery Studio Suite. We have developed working hypotheses for binding of small molecules to a variety of biomolecular targets including the allosteric site of metabotropic glutamate receptors, the human ATP binding cassette, and the quadruplex DNA conformer of the c-myc oncogene.

Projects

Contributions to Science (selected from 102 peer reviewed publications).

Organic Synthetic methods: hydrides of boron and lanthanides in organic synthesis

A hydride is among the smallest groups that can be introduced into a molecule, however, the selectivity of this process is of fundamental importance. During my graduate work with the late Robert O. Hutchins, I was inspired by his guidance, and learned from his enthusiasm and persistence, but also was mentored in the use of mechanisms to guide and optimize synthetic methods. The Hutchins group was focused on reproducibility, and a paper in Organic Synthesis - which requires replication - was highly valued (I had one). In my experience, R.O. Hutchins had no peer at recrystallization (in my experience), and if a small molecule diffractometer had been available to him at that time, he would have had hundreds of additional crystallography papers. Hutch advised that I post-doc in the emerging field of asymmetric synthesis, and look for a new direction as I began my first independent position. The f-block elements in organic synthesis were of interest, and what could be more fundamental than a single electron transfer? We continue to use lanthanide catalysts whenever they seem to potentially provide improved reactivity, and also returned to our roots in hydrides of boron recently to provide authentic substrates for DMPK studies of isoxazoles of potential medicinal application (which was dedicated to two other Hutchins group alumni).

a. R.O. Hutchins and N.R. Natale, Cyanoborohydride. Utility and Synthetic Applications in Organic Synthesis. A Review. Org. Prep. Proced., Int., 1979, 11,  201-246. This remains one of my most highly cited papers.

b. N.R. Natale, Selective Reduction of Isoxazoles with Samarium Diiodide. Tetrahedron Lett., 1982, 5009-5012.

c. P. Zhou, J.E. Blubaum, C.T. Burns and N.R. Natale, The Direct Synthesis of 2-Oxazolines from Carboxylic Esters using Lanthanide Chloride as Catalyst. Tetrahedron Lett.,1997, 38, 7019-7020.

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

Hypothesis-driven Structure based drug design

From our early work on Dihydropyridine anti-hypertensives (vide infra), we sought to use computational methods to develop rational working hypotheses in silico. This began with the study of ligand conformation (using programs on tape from the Quantum Chemistry Program Exchange) to develop ligand based models (Kovacic, 1990), and developed over time to docking programs. Our quadruplex DNA computations began with Silicon Graphics Indigo II (Han, 2002), and the project has evolved through SYBYL and AutoDock VIna, to our recent sabbatical experience with the CHARMM forcefield and the Discovery Studio Suite (Steiger, 2015; Gates, 2015). Structure based drug design is now a routine tool in medicinal chemistry, yet no single program can yet rank a series of ligands accurately for all biomolecular targets. To mine the wealth of data from x-ray and NMR in the pdb, computational methods will continue to represent an important hypothesis generator, in concert with consensus scoring to evaluate ensembles of calculated docking results, but will demand the development of new chemistries to test and evaluate these hypotheses experimentally.

a. Kovacic, P.; W. Daniel Edwards, N.R. Natale, R. Sridhar, P. Kiser, Structure Calculations on Calcium Channel Drugs: Is Electron Transfer Involved Mechanistically?, Chem. Biol. Interactions, 1990, 75, 61-70. PMID: 2364458.

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

c. Steiger, S.A.; Chun Li,  Donald S. Backos, Philip R. Reigan, and N.R. Natale, Of mice and men: MDR-1 ligands docked at a human ABC transporter, 70th ACS Northwest Regional Meeting, June 21 - 24, 2015, Idaho State University, Pocatello, Idaho. Abstract 44.

d. Gates, C.; Donald S. Backos, Philip R. Reigan, Chris Koerner, Joseph Mirzaei, and N.R. Natale, Isoxazolo [3,4-d] pyridazinones modeled at the allosteric metabotropic Glutamate receptor site. 70th ACS Northwest Regional Meeting, June 21 - 24, 2015, Idaho State University, Pocatello, Idaho. Abstract 45.

Aryl Isoxazole amide (AIM) antitumor agents

The c-myc oncogene is a master regulator of gene expression, and adopts a unique conformation, a G-4 quadruplex, which may allow for selective stabilization by small molecule ligands. Again novel chemistry gave rise to novel biology, as sterically hindered aryl isoxazoles were constructed by a lanthanide catalyzed double activation, and provided entry into antitumor agents with a novel mechanism of action. Our most recent generation of compounds possess nanomolar antitumor activity. This odyssey has lured us into many adventures: fluorescence microscopy, flow cytometry, telomerase repeat assays, CD melting temperatures, oligonucleotide NMR among others, techniques far afield from what some colleagues refer to as my bucket chemistry. This represents a stimulating interdisciplinary environment for student learning.

a. Peiwen Zhou, M.D. Mosher, Wendy D. Taylor, Gregory A. Crawford, NataleN.R. Double Activation Preparation of an Acridinyl - Isoxazolyl- Lexitropsin. Bioorg. & Med. Chem. Lett.19977, 2455-2456.

b. Xiaochun Han, Chun Li, Kevin C. Rider, Alex Blumenfeld, Brendan Twamley, and N.R. Natale, The Isoxazole as a linchpin for molecules which target folded DNA conformations: Selective Lateral Lithiation and Palladation. Tetrahedron Lett., 200243, 7673-7677.

c. X. Han, Chun Li, M.D. Mosher, K. C. Rider, P. Zhou, Ronald L. Crawford, William Fusco, Andrzej Paszczynski, N.R. Natale, Design, Synthesis and Biological Evaluation of A Novel Class of Anticancer Agents: Anthracenylisoxazole Lexitropsin Conjugates. Bioorg. Med. Chem., 200917,1671-1680.

d. Matthew J. Weaver, Alison K. Kearns, Sascha Stump, Chun Li, Mariusz P. Gajewski, Kevin C. Rider, Donald S. Backos, Philip R. Reigan, Howard D. Beall, N.R. Natale, AIMing towards Improved Antitumor Efficacy. Bioorg. Med. Chem. Lett. 201525,1765-1770. NIHMS 672906. PMID: 25782743.

Dihydropyridine antihypertensives and MDR ligands

My interest in 4-aryl-1,4-dihydropyridines began with my post-doctoral work in the labs of A.I. Meyers, where we achieved the first practical chiral adjuvant asymmetric synthesis of 4-aryl-DHPs. In my first independent position at the University of Idaho, we developed the bioisosteric 4-isoxazolyl-dihydropyridines (IDHPs), which were robust calcium antagonists, in collaboration with Dr. David Triggle. We discovered a significant eudismic ratio for the IDHPs at the voltage gated calcium channel, using the synthetic tools of lateral metalation and stoichiometric asymmetric synthesis, and elucidated a unique structure activity relationship (SAR) for the IDHPs. More recently, we have uncovered activity at the multi-drug resistance transporter (MDR-1), with a distinct SAR which holds promise for the development of selective ligands at this efflux transporter. Our recently developed asymmetric organocatalytic synthesis of IDHPs (Scott Steiger, Ph.D. Dissertation, University of Montana, Dec. 2014) will allow for further SAR exploration of the stereoselective biological action for this useful scaffold.

a. A.I. Meyers, N.R. Natale, Wettlaufer, D.G.; S. Rafii, and J.C. Clardy, Chiral 1,4-Dihydropyridines. Synthesis and Absolute Configuration. Tetrahedron Lett., 1981, 5123-5126.

b. N.R. Natale, David J. Triggle, Robert B. Palmer, Barbara J.Lefler and W. Daniel Edwards, 4-Isoxazolyl-Dihydropyridines: Biological, Theoretical and Structural Studies. J. Med. Chem., 1990, 33, 2255-9. PMID: 2142737.

c. Gerald Zamponi, Stephanie C. Stotz, Richard J. Staples, Tina A. Rogers, Jared K. Nelson, Victoria Hulubei, Alex Blumenfeld, Natale, N.R.  Unique Structure Activity Relationship of 4-Isoxazolyl-1,4-dihydropyridines. J.  Med. Chem., 2003, 46, 87-96. PMID: 12502362.

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

Glutamate Receptors and transporters

Glutamate is a significant neurotransmitter, the most abundant in the human CNS. Our entry into this arena was enabled by novel synthetic methodology, which allowed for a more efficient catalytic asymmetric synthesis of glutamate analogs targeted toward ionotropic glutamate receptors in the AMPA class. During systematic SAR studies we uncovered a unique selectivity for the system Xc- glutamate/cystine antiporter (SxcT), and recently have discovered allosteric modulators of SxcT. Allosteric modulators comprise 30% of medicines, and appear to offer more opportunity for selectivity in comparison to the more conserved orthosteric binding domain. We have entered into a licensing agreement with Promentis Pharmaceuticals to pursue small molecule leads with plausible medicinal applications at SxcT, and have active interest in glutamate receptors and transporters.

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

b. N.R. Natale, K. Magnusson, and J.K. Nelson, Structural Basis for Glutamate Recognition: Can Small Molecules which Bind Selectively be Developed? Current Topics Med. Chem., 2006, 6, 823-846.

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

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

Chemical Education

Organic chemistry is a tradition of teachers. Research, and notably undergraduate research, is a particularly effective arena for teaching active learning and critical thinking. Undergraduates have made a significant contribution to my research efforts over the years, and progress at remote mountain west universities would not have been practical without them. Alumni from my group have gone on to both pharma and academia, and include a company president, several pharma group leaders and two full professors among the baker's dozen who have gone on to further the tradition of teachers in college level academics.

a. K. Dean Bowles, David A. Quincy, Brenda Mallet, John I. McKenna and Natale, N.R. Heterocycles and Reactive Intermediates in the Undergraduate Organic Lab. J. Chem. Ed., 1985, 62, 1118-20.

b. M.D. Mosher, E.J. Verner, B.J. Oliver, Daniel Hamlin, N. Vietri, R.B. Palmer, T.V. Arnold, Natale, N.R. Synthesis of N-Methyl-2-trichloroacetyl-pyrrole. A Key Building Block in Peptides that Bind DNA. Micro-,Semi-micro, and Macro-scale Organic Lab Experiments. J. Chem. Ed., 1996, 1036-1039.

c. N. R. Natale, invited contribution, Building Bridges to Native American Students: Chapter Outreach Activities at the University of Idaho. in Chemistry (American Chemical Society), 2002, 12, November/December, 15-17.

d. N.R. Natale, H.D.Beall, How to pdb: a class exercise for professional Pharmacy Med Chem. 249th ACS National Meeting, March 23, 2015, Denver, CO. CHED 174. Sci-Mix.

Selected Patents and Disclosures

"Hydroxamic Acid Crown Ethers", N.R. Natale, S. Elshani and C.M. Wai, U.S. Patent No. 5,274,129, issued December 28, 1993.

“h6 Metal Complexes of 4-Aryl-1,4-Dihydropyridines”, N.R. Natale; Bitterwolf, Thomas, E.; Hubler, Timothy, International Application No. PCT/US1993/002682, Filing Date: March 19, 1993.

"Alkyl, Alkyl-Ether, Aryl or Aryl-Ether Hydroxy Proline Derivatives as Inhibitors of the Amino Acid Transporter ASCT2 (SLC1A5)", Brent Lyda, C.S. Esslinger, N.R. Natale and M. Kavanaugh, UM Technology Transfer Office, The University of Montana, Date of disclosure: September 27, 2010. U.S. Provisional Patent Application No. 61/508,512, filed July 15, 2011."Novel Inhibitors of the Amino Acid Transporters ASCT1 and ASCT2", C.S. Esslinger, M. Kavanaugh, Brent Lyda, N.R. Natale. US Patent 8,895,607, filing date: July 16, 2012, issued November 25, 2014.

"Novel Isoxazoles as Allosteric Inhibitors of System Xc-transporter", N.R. Natale, R.J. Bridges, S.A. Patel, UM Technology Transfer Office, The University of Montana, Date of disclosure: June 13, 2014. U.S. Provisional Patent Application US 62/015,178, June 20, 2014. "Novel Inhibitors of System Xc(-)", Patent application No. 14/744,707, Filing date: June 19, 2015, Licensed to Promentis.

 

Selected Publications

  • Matthew J. Weaver, Alison K. Kearns, Mariusz P. Gajewski, Kevin C. Rider, Chun Li, Donald S. Backos, Philip R. Reigan, Howard D. Beall, N.R. Natale, AIMing toward improved antitumor efficacy. Bioorg. Med. Chem. Lett., 2015, 25, 1765-1770. NIHMS 672906. PMID: 25782743.
  •  Scott A. Steiger, Anthony J. Monacelli, Chun Li, Janet L. Hunting, N.R. Natale, The effect of bromine scanning around the phenyl group of 4-phenyl-hexahydroquinolone derivatives. Acta Cryst., 2014, C70, 790-795. PMID: 25093361.
  • Natale, N.R. and Steiger, S.A.  4-Isoxazolyl-1,4-dihydropyridines: a tale of two scaffolds,Future Med. Chem., invited review, 2014, 6(8), 923-943.PMID: 24962283.
  • Scott A. Steiger, Anthony J. Monacelli, Chun Li, Janet L. Hunting and N. R. Natale, Diethyl 4-(biphenyl-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate. Acta Cryst., 2014, E70,  o791-o792. doi:10.1107/S1600536814013294.
  •  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. NIHMS 551141. PMID: 24342237.
  • Nathan S. Duncan, Howard D. Beall, Alison K. Kearns, Chun Li and N.R. Natale, Ethyl 3-(9'-chloro-10'-oxo-9',10'-dihydroanthracen-9'-yl)-5-methylisoxazole-4-carboxylate. Acta Cryst, 2014, E70, o315-o316. PMID: 24765016.
  • J. Newell, C.M. Keyari, P. Diaz, N.R. Natale, S. Patel, R. Bridges, Novel Di-aryl-substituted Isoxazoles act as noncompetitive inhibitors of the Xc- Glutamate Cystine exchanger. Neurochem. International2014, 73, 132-138.PMID: 24333322.
  •  Chun Li, Michael J. Campbell, M.J. Weaver, N.S. Duncan, Janet L. Hunting and N.R. Natale, Ethyl 3-(10-bromo-anthracen-9-yl)-5-methyl-1,2-oxazole-4-carboxylate. Acta Cryst., 2013, E69, o1804-o1805. PMID: 24860293.
  •  Campana, C.; Mirzaei, J.; Koerner, C.; Gates, C.; Natale, N.R. 3-(1,3-Diphenylpropan-2-yl)-4-methyl-6-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one. Acta Cryst., 2013, E69, o1680-o1681. PMID: 24454112.
  • Afnan A. Matti, J. Mirzaei, John Rudolph, Stephen A. Smith, J. Newell, S.A. Patel, M. Braden, R.J. Bridges, and N.R. Natale, Microwave accelerated synthesis of Isoxazole inhibitors of the System xc- transporter: initial homology model". Bioorg. Med. Chem. Lett., 2013, 23, 5931-5935. NIHMS 527036. PMID: 24042010.
  •  Yousef R. Mirzaei, Matthew J. Weaver, Scott A. Steiger, Alison K. Kearns, Mariusz P. Gajewski, Kevin C. Rider, Howard D. Beall, and N.R. Natale, Improved synthesis of 3-aryl isoxazoles containing fused aromatic rings. Tetrahedron, 2012, 68, 10360-10364. Pubmed Central NIHMS410467.
  • 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. PMID: 23063517.
  •  Richard J. Bridges, N.R. Natale, Sarjubhai A. Patel, System xc- Glutamate/Cystine Antiporter:  An Update on Molecular Pharmacology and Roles Within the CNS. British J. Pharm., 2012, 165, 20-34. PMID: 21564084.
  •  Steven W. McDaniel, Charles M. Keyari, Kevin C. Rider, N.R. Natale and Philippe Diaz, Suzuki-Miyaura Cross-Coupling of Benzylic Bromides Under Microwave Conditions. Tetrahedron Lett., 2011, 52, 5656-5658. PMID: 21966033.
  • Kevin C. Rider, David J. Burkhart, Chun Li, Andrew R. McKenzie, Jared K. Nelson, and N.R. Natale, Preparation of chiral isoxazole carbinols via catalytic asymmetric Corey-Bakshi-Shibata reduction. ARKIVOC, 2010, part (viii), pages 97-107. Commemorative issue in honor of Drs. Bruce E. and Cynthia A. Maryanoff.
  • Sarjubhai A. Patel, Trideep Rajale, Erin O’Brien, David J. Burkhart, Jared K. Nelson, Brendan Twamley, Alex Blumenfeld, Monika I. Szabon-Watola, John M. Gerdes, Richard J. Bridges, and N.R. Natale, Isoxazole analogues bind the System xcTransporter: Structure-activity Relationship and Pharmacophore Model. Bioorg. Med. Chem., 2010, 18, 202-213. PMID: 19932968.
  •  Mariusz P. Gajewski, Howard Beall, Mark Schnieder, Sarah M. Stranahan, Michael D. Mosher, Kevin C. Rider, and N.R. Natale, Bis-Anthracenyl Isoxazolyl Amides have Enhanced Anticancer Activity.  Bioorg. Med. Chem. Lett. 2009, 19, 4067-4069. PMID: 19560922.
  •  Xiaochun Han, Chun Li, Michael D. Mosher, Kevin C. Rider, Peiwen Zhou, Ronald L. Crawford, William Fusco, Andrzej Paszczynski, and N.R. Natale, Design, Synthesis and Biological Evaluation of A Novel Class of Anticancer Agents: Anthracenylisoxazole Lexitropsin Conjugates. Bioorg. Med. Chem., 2009, 17, 1671-1680. Pubmed Central NIHMS99529. PMID: 19167892
  • Jared K. Nelson, Brendan Twamley, Trinidad J. Villalobos, and N.R. Natale, The Catalytic Asymmetric Addition of Alkyl- and Aryl- zinc Reagents to an Isoxazolyl Aldehyde. Tetrahedron Lett., 2008, 49, 5957-5960.
  • Jared K. Nelson, Christopher T. Burns, Miles P. Smith, Brendan Twamley and N.R. Natale, Synthetic Utility of Epoxides for Chiral Functionalization of Isoxazoles. Tetrahedron Lett., 2008, 49, 3078-82.
  • Chun Li, Brendan Twamley and N.R. Natale, Preparation and Crystal Structures of Two 3-Anthracenyl Isoxazolyl Sulfonamides. J. Heterocycl. Chem., 2008, 45, 259-264.
  • 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.
  • 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.
  • Isoxazole Ionotropic Glutamate Neurotransmitters, David J. Burkhart and N.R. Natale, Current Medicinal Chemistry, invited review, 2005, 12, 617-627.
  • 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.
  • 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.
  • 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.