Christopher Comer, Dean
Professor of ChemistryEmail: email@example.com
Office: Chem 312A
Nigel Priestley came to the University of Montana in 1999 from the Ohio State University. He earned his Ph.D. on organic chemistry from The University of Southampton, UK in 1991 and did postdoctoral studies at the University of Washington. While at Ohio State University he was an Assistant Professor in the Division of Medicinal Chemistry and Pharmacognosy.
Antibiotic/Anticancer Drug Development
Historically, the discovery of antibiotic lead compounds has been greatly aided by the study of natural products. Despite natural products' preeminence, however, there are well known hurdles to their development as drugs. Many are only available in trace amounts and their structures are not amenable to cost effective de novo synthesis. While Nature often provides close structural analogs of a natural product they are often produced in very low quantities and the developer has to rely upon a set of compounds that are not necessarily an optimal set for effective SAR evaluation. Furthermore, chemists have a limited ability to alter the structures generated in Nature in a general and reliable way. Where modification is possible, however, such semi-natural compounds are among the most successful of drugs (penicillin derivatives, azithromycin), but each starting lead is optimized individually by reliance on the chemical handles that are found serendipitously in the structure.
Our successful research strategy has been to leverage the structural diversity of natural products in the search for new structures with biological activity. We recognize that natural products contain privileged structural motifs that have been repeatedly selected for by evolution. We choose natural products that are readily available in scale through fermentation thereby avoiding the issues of limited availability. We chemically degrade these structures to generate structurally and stereochemically complex building blocks in scale and then generate combinatorial libraries of new chemical entities that combine the complexity of natural products with the scale and diversity traditional synthesis. The compounds that are generated are natural product-like and are not in any way limited in scope to the activity of the parent natural compound. We use our libraries to discover new biological activity through screening. We use libraries only to generate initial hits and then use medicinal chemistry to thoughtfully optimize the hit structure to develop a lead compound.
Nonactin is a macrocyclic, polyether, ionophore antibiotic with a stereochemically complex structure. We obtain nonactin by fermentation, degrade the compound to obtain nonactic acid and then use nonactic acid as the core pharmacophore to produce triazolononactates, a structurally novel antibiotic class with activity against Gram positive pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Ongoing work includes the continued optimization of the class through iterative rounds of synthesis and evaluation and the determination of the biological target through microbioogical and biochemical approaches.
Dihydrofolate reductase inhibitors
Dihydrofolate reductase (DHFR) catalyzes the formation of tetrahydrofolate from dihydrofolate, a reaction that is required for the de novo synthesis of purines, thymidilic acid and amino acids. The antibiotic Bactrim (trimethoprim/sulfamethoxazole) inhibits the action of DHFR. While resistance to Bactrim is becomming quite common, there are limited options in second generation Bactrim analogs for overcoming resistance. We have collaborated for many years with Professors Amy Anderson and Dennis Wright at the University of Connecticut and Professor Stephen Bergmeier at Ohio University to develop interesting trimethoprim analogs that are potent, selective and have promise as clinical candidates.
Compound libraries built from stereochemically complex bioblocks
Combinatorial and parallel synthesis have been successful in generating lead compounds in many therapeutic areas with the notable exception of antibiotics. There are many structural features common to antibiotics, for example stereochemical and topological complexity, that are not captured well in large libraries of synthetically-derived compounds. To address this we are generating small, stereocomplex, natural product-derived building blocks obtained from polyethers, terpenes and alkaloids and using these to rapidly assemble libraries of novel natural product-like structures for use in screening campaigns.
Inhibitors of DNA methyltransferase I
Epigenetic methylation of cytosine in DNA occurs at CpG sites and in dense clusters of CpG dinucleotides within gene promoters and is catalyzed by DNA methyltransferase enzymes (DNMT’s) which transfer a methyl group from S-adenosylmethionine to the 5-position of cytosine to yield 5-methylcytosine. While there are four main classes of DNMT, DNMT-1 is the main maintenance methylase responsible for maintaining gene expression patterns following cell division. Therapies that can selectively inhibit DNMT-1 and reverse hypermethylation phenotypes, thereby reactivating the normal cell cycle and apoptotic machinery, would be of significance. We are developing, using a combination of medicinal chemistry, 3D QSAR and crystallography, a series of novel inhibitors based upon the isoindolinone scaffold found in the natural products stachybotrymide and porritixin.
The Berkeleylactones, antibiotic macrolides from fungal coculture. Andrea A. Stierle, Donald B. Stierle, Daniel Decato, Nigel Priestley, Jeremy Alverson, John Hoody, Kelly McGrath and Dorota Klepacki,; J. Nat. Prod. (2017), 80(4), 1150–1160.
Pharmaceutical analysis of a novel propargyl-linked antifolate antibiotic in the mouse. John Hoody, Jeremy B. Alverson, Santosh Keshipeddy, Patrick A. Barney, Larissa Walker, Amy C. Anderson, Dennis L. Wright and Nigel D. Priestley. J. Chromatog. B. (2017), 1051, 54–59.
Charged nonclassical antifolates with activity against gram-positive and gram-negative pathogens. Scocchera, Eric; Reeve, Stephanie M.; Keshipeddy, Santosh; Lombardo, Michael N.; Hajian, Behnoush; Sochia, Adrienne E.; Alverson, Jeremy B.; Priestley, Nigel D.; Anderson, Amy C.; Wright, Dennis L. ACS Medicinal Chemistry Letters (2016), 7(7), 692-696.
Crystal structures of Klebsiella pneumoniae dihydrofolate reductase bound to propargyl-linked antifolates reveal features for potency and selectivity. Lamb, Kristen M.; Lombardo, Michael N.; Alverson, Jeremy; Priestley, Nigel D.; Wright, Dennis L.; Anderson, Amy C. Antimicrobial Agents and Chemotherapy (2014), 58(12), 7484-7491.
De novo macrolide-glycolipid macrolactone hybrids: synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles. Desmond, Richard T.; Magpusao, Anniefer N.; Lorenc, Chris; Alverson, Jeremy B.; Priestley, Nigel; Peczuh, Mark W. Beilstein Journal of Organic Chemistry (2014), 10, 2215-2221.
Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata. G-Dayanandan, Narendran; Paulsen, Janet L.; Viswanathan, Kishore; Keshipeddy, Santosh; Lombardo, Michael N.; Zhou, Wangda; Lamb, Kristen M.; Sochia, Adrienne E.; Alverson, Jeremy B.; Priestley, Nigel D.; Wright, Dennis L. and Anderson, A. C. J. Med. Chem. (2014), 57(6), 2643–2656.
Toward new therapeutics for skin and soft tissue infections: propargyl-linked antifolates are potent inhibitors of MRSA and Streptococcus pyogenes. Kishore Viswanathan, Kathleen M. Frey, Eric W. Scocchera, Brooke D. Martin, P. Whitney Swain III, Jeremy B. Alverson, Nigel D. Priestley, Amy C. Anderson and Dennis L. Wright, PLoS One, 2012, 7(2), e29434.
The furan route to tropolones: probing the antiproliferatve effects of beta-thujaplicin analogs. Zachary E. Oblak, Erin S. D. Bolstad, Sophia N. Ononye, Nigel D. Priestley, Hadden M. Kyle and Dennis L. Wright, Organic and Biomolecular Chemistry 2012, 10(43), 8597–8604.
Synthesis of a functionalized oxabicyclo[2.2.1]heptane-based chemical library. Sarah B. Luesse, Gregg Wells, Jeanne Miller, Erin Bolstad, Stephen C. Bergmeier, Mark C.
McMills, Nigel D. Priestley, and Dennis L. Wright, Combinatorial Chemistry & High
Throughput Screening, 2012, 15(1), 81-89.
Natural feedstocks for diversity-oriented synthesis: macrolide scaffolds from nonactate. Yuliya G. Sumskaya, P. Whitney Swain III, Stephen C. Bergmeier, Mark C. McMills, Nigel D.
Priestley and Dennis L. Wright, ARKIVOC, 2011, (5), 144-166.
Nonactin biosynthesis: Unexpected patterns of label incorporation from 4,6-dioxoheptanoate show evidence of a degradation pathway for levulinate through propionate in Streptomyces griseus. Jian Rong, Michael E. Nelson, Brian Kusche and Nigel D. Priestley, J. Nat. Products, 2010, 73(12), 2009-2012.
Natural product derivatives with bactericidal activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. Joshua B. Phillips, Adrienne E. Smith, Brian R. Kusche, Bradley A. Bessette, P. Whitney Swain
III, Stephen C. Bergmeier, Mark C. McMills, Dennis L. Wright and Nigel D. Priestley, Bioorg.
Med. Chem. Letts., 2010, 20(19), 5936-5938.
Specialized Research Interests
Natural product chemistry, biochemistry, and biosynthesis; antibiotic and anticancer therapeutic development.