John D. Chisholm

Associate Professor, Chemistry


Research Interests

organic chemistry, medicinal chemistry, synthesis, catalysis, organometallic chemistry




Education

  • B.S., 1992, Alma College
  • Ph.D., 2000, University of California, Irvine
  • Postdoctoral Fellow, 2000-2002, Stanford University




Honors & Awards

  • Editorial Board, Scientific Reports, 2016-present
  • Scientific Advisory Board, Alterna Therapeutics, 2016-present
  • Nappi Family Research Award, 2015-2016
  • NIH Academic Research Enhancement Award, 2015-2018
  • Editorial Board, Current Catalysis, 2015-present
  • National Institute of Health Postdoctoral Fellowship, 2000-2002
  • Bristol-Myers Squibb Graduate Fellowship, 1999-2000




Courses

  • CHE 275: Organic Chemistry
  • CHE 575: Organic Spectroscopy
  • CHE 675: Advanced Organic Chemistry
  • CHE 676: Introduction to Organic Synthesis: Methodology
  • CHE 686: Introduction to Organic Synthesis: Design
 




Research Focus

Research in the Chisholm group is focused on organic chemistry, broadly defined. This includes studies in medicinal chemistry, catalysis and natural products synthesis. Current projects include:

1. Medicinal chemistry on small molecule modulators of the inositol phosphatase SHIP

2. The exploration of new synthetic methods

3. The synthesis of complex natural products

Medicinal Chemistry

In collaboration with the Kerr laboratory at SUNY Upstate Medical University, we have been developing new inhibitors of the SH2-containing Inositol 5’-Phosphatase SHIP. SHIP is a phosphatase that selectively removes a phosphate from the 5’ position of the inositol substrate PI(3,4,5)P3. The phosphorylation pattern on these inositols act as control elements in passing signals from the outside of the cell membrane to the nucleus of the cell, which is turn influence migration, growth and survival (Figure 1). By influencing the activity of the phosphatase SHIP a number of these important cellular events can be regulated. This regulation may be beneficial for a number of disease states, including cancer, diabetes, and anemia. Therefore small molecule inhibitors of SHIP are of great interest.
  
Chisholm_1
Figure 1. The role of SHIP in cellular signaling
    

A number of small molecule inhibitors of SHIP have been found by high throughput screening (Figure 2A). Medicinal chemistry studies have now commenced on these structures to improve the potency and pharmacodynamic properties of these molecules so that they may be used to probe the role of SHIP in a number of in vitro and in vivo model systems. Currently a number of approaches are being used to facilitate these studies, including complex molecule synthesis and in silico docking studies on the active site of the enzyme (Figure 2B).

    
Chisholm_2
Figure 2. A) The structures of small molecule inhibitors of SHIP found through high throughput screening.
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Figure 2. B) An inhibitor (blue) bound to the crystal structure of the active site of SHIP (shown in green) in silico.



Development of New Synthetic Methods

Our initial forays into new methods focused on the transition metal catalyzed reactions of alkynes (Figure 3). Rhodium catalysis was effective in the 1,4-addition of alkynes to a,b-unsaturated ketones. Interestingly, changing the ligand to the tri-o-tolylphosphine lead to the formation of an alkyne dimerization-addition product instead of the 1,4-addition product. These reactions occur under mild conditions that are tolerant of functional groups (alcohols, ketones, carboxylic acids, etc.) that have to be protected under standard conditions. Rhodium-catalyzed addition of alkynes to enolizable 1,2-diketones and 1,2-ketoesters are also notable, as these substrates are problematic because they enolize readily (protecting them from attack) and often self-condense. Palladium catalysis was found to be effective for the addition of alkynes to strained rings, such as cyclopropenes. The alkynylcyclopropane products provide ready access to vinylcyclopropanes, which are valuable synthetic intermediates.

    
Chisholm_3
Figure 3. New transition metal mediated reaction of alkynes

 

  

Complex Molecule Total Synthesis

We are also interested in developing new synthetic routes to complex molecules with interesting biological activity. Some targets that are currently of interest are shown below (Figure 4). These studies provide material to explore the biological properties of these molecules. Many of these molecules are natural products, which have long been a primary source of therapeutic agents and candidate molecules.

 

Chisholm_4
Figure 4. Natural product targets.




Selected Publications

Hoekstra, E.; Das, A.; Willemsen, M.; Swets, M.; Kuppen, P. J. K.; van der Woude, C. J.; Bruno, M. J.; Shah, J. P.; ten Hagen, T.; Chisholm, J. D.; Kerr, W. G.; Peppelenbosch, M. P.; Fuhler, G. M. "The lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation." Oncotarget 2016, Advance Online Publication, (published September 28, 2016). DOI:10.18632/oncotarget.12321

Wallach, D. R.; Chisholm, J. D. “Alkylation of Sulfonamides with Trichloroacetimidates Under Thermal Conditions.” J. Org. Chem. 2016, 81, 8035-8042. DOI:10.1021/acs.joc.6b01421   

Adhikari, A. A.; Chisholm, J. D. "Lewis Acid Catalyzed Displacement of Trichloroacetimidates in the Synthesis of Functionalized Pyrroloindolines." Org. Lett. 2016, 18, 4100-4103. DOI:10.1021/acs.orglett.6b02024

Srivastava, N.; Iyer, S.; Sudan, R.; Youngs, C.; Engelman, R. W.; Howard, K. T.; Russo, C. M.; Chisholm, J. D.; Kerr, W. G. “A small-molecule inhibitor of SHIP1 reverses age- and diet-associated obesity and metabolic syndrome.” JCI Insight. 2016, 1, e88544. DOI:10.1172/jci.insight.88544

Howard, K. T.; Chisholm, J. D. “Preparation and Applications of 4-Methoxybenzyl Esters in Organic Synthesis.” Org. Prep. Proced. Int. 2016, 48, 1-36. DOI:10.1080/00304948.2016.1127096

Howard, K. T.; Duffy, B. C.; Linaburg, M. R.; Chisholm, J. D. “Formation of DPM Ethers Under Neutral Conditions Using Diphenylmethyl Trichloroacetimidate.” Org. Biomol. Chem. 2016, 14, 1623-1628. DOI:10.1039/c5ob02455b

Russo, C. M.; Adhikari, A. A.; Wallach, D. R.; Fernandes, S.; Balch, A. N.; Kerr, W. G.; Chisholm, J. D. “Synthesis and Initial Evaluation Quinoline-Based Inhibitors of SHIP.” Bioorg. Med. Chem. Lett. 2015, 25, 5344-5348. DOI:10.1016/j.bmcl.2015.09.034

Fernandes, S.; Brooks, R.; Park, M-Y.; Srivastava, N.; Russo, C. M.; Howard, K. T.; Chisholm, J. D.; Kerr, W. G. “SHIP Inhibition Enhances Murine Autologous and Allogeneic Hematolymphoid Cell Transplantation.” EBioMedicine 2015, 2, 205-213. DOI:10.1016/j.ebiom.2015.02.004

Duffy, B. C.; Howard, K. T.; Chisholm, J. D. “Alkylation of Thiols using Trichloroacetimidates under Neutral Conditions.” Tetrahedron Lett. 2015, 56, 3301-3305. DOI:10.1016/j.tetlet.2014.12.042

Corcoran, J. T.; Carberry, P.; Viernes, D. R., Chisholm, J. D. “Intramolecular Diels-Alder Reactions Utilizing Aldehyde and Ketone Dienophiles. A Rare Variant of the Diels-Alder Reaction.” Mini-Rev. Org. Chem. 2015, 2, 149-161. DOI:10.2174/1570193X11666141029000030

Wallach, D. R.; Stege, P. C.; Shah, J. P.; Chisholm, J. D. “Selective Monoalkylation of Anilines with Trichloroacetimidates.” J. Org. Chem. 2015, 80, 1993-2000. DOI:10.1021/jo5027222

Brooks, R.; Iyer, S.; Akada, H.; Russo, C. M.; Chisholm, J. D.; Kerr W. G. “Coordinate Expansion of the Hematopoietic and Mesenchymal Stem Cell Compartments by SHIPi.” Stem Cells, 2015, 33, 848-858. DOI:10.1002/stem.1902

Viernes, D. R.; Choi, L. B.; Kerr, W. G.; Chisholm, J. D. “Discovery and Development of Small Molecule SHIP Phosphatase Modulators.” Med. Res. Rev. 2014, 34, 795-824. DOI:10.1002/med.21305

Adhikari, A. A.; Shah, J. P.; Howard, K. T.; Russo, C. M.; Wallach, D. R.; Linaburg, M. R.; Chisholm, J. D. “Convenient Formation of DPM Esters Using Diphenylmethyl Trichloroacetimidate.” Synlett 2014, 283-287. DOI:10.1055/s-0033-1340293

 

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