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).

    
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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

Recent investigations into the reactivity of trichloroacetimidates have also been fruitful (Figure 3). Trichloroacetimidates are known to be excellent alkylating agents when activated by a catalytic amount of a Brønsted acid. Some preliminary forays into this area showed that many imidates are much more reactive than predicted by early studies, with carboxylic acids, alcohols and thiols being alkylated by the imidates without the need for a catalyst. In addition, other nucleophiles like anilines and sulfonamides have been shown to be competent nucleophiles in the presence of an acid catalyst. The alkylation of carboxylic acids and alcohols appears to be limited to more reactive imidates, but is still useful in the installation of PMB and DPM protecting groups. The alkylation of anilines and thiols has a wider substrate scope. Preliminary studies have shown that these new trichloroacetimidate substitution reactions are less prone to competing elimination than methods using sulfonate-leaving groups. Additionally, these imidate substitution reactions may be amenable to asymmetric catalysis.

    
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Figure 3. New substitution reactions with trichloroacetimidates

 

  

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.

 

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Figure 4. Natural product targets.




Selected Publications

Adhikari, A. A.; Suzuki, T.; Gilbert, R. T.; Linaburg, M. R.; Chisholm, J. D. "Rearrangement of Benzylic Trichloroacetimidates to Benzylic Trichloroacetamides." J. Org. Chem. 2017In press, accepted article preview online March 21, 2017. DOI:10.1021/acs.joc.7b00245

Itkin, T.; Kumari, A.; Gur-Cohen, S.; Ludwig, C.; Brooks, R.; Golan, K.; Khatib, E.; Hornstein, E.; Russo, C. M.; Chisholm, J. D.; Kerr, W. G.; Kuchenbauer, F.; Lapidot, T. "MicroRNA-155 promotes G-CSF-induced mobilization of murine hematopoietic stem and progenitor cells via propagation of CXCL12 signaling." Leukemia 2017, In press, accepted article preview online February 8, 2017. DOI:10.1038/leu.2017.50

McGovern-Gooch, K.; Mahajani, N. S.; Garagozzo, A.; Schramm, A. J.; Hannah, L. G.; Sieburg, M. A.; Chisholm, J. D.; Hougland, J. L. “Synthetic Triterpenoid Inhibition of Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation.” Biochemistry 2017, 56, 919-931DOI:10.1021/acs.biochem.6b01008

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, 7, 73525-73540. 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 of quinoline-based inhibitors of the SH2-containing inositol 5'-phosphatase (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

 

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