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John D. Chisholm

John D. Chisholm


Professor,
Chemistry

jdchisho@syr.edu

4-006 Center for Science and Technology
315.443.6894


    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.
    chisholm_2b
    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.

    Chisholm_3

    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.

    Chisholm_4
    Figure 4. Natural product targets

    Selected Publications

    • Mahajani, N. S.; Chisholm, J. D. " Catalyst Free Allylation of Trichloroacetimidates with Allyltributylstannane Under Thermal Conditions to Access the Common 1,1’-Diarylbutyl Pharmacophore." Org. Biomol. Chem. 2018, 16, 4008-4012. DOI:10.1039/C8OB00687c
    • Mahajani, N. S.; Chisholm, J. D. " Synthesis of 1,1’-Diarylethanes and Related Systems by Displacement of Trichloroacetimidates with Trimethylaluminum." J. Org. Chem. 2018, 83, 4131-4139. DOI:10.1021/acs.joc.8b00027
    • Wilhelmsen, C. A.; Dixon, A. D. C.; Chisholm, J. D.; Clark, D. A. “Synthesis of N-Substituted-3-amino-4-halopyridines: a Sequential Boc-Removal/Reductive Amination Mediated by Brønsted and Lewis Acids.” J. Org. Chem. 2018, 83, 1634-1642. DOI:10.1021/acs.joc.7b02966
    • Dushukyan, N.; Dunn, D. M.; Sager, R. A.; Woodford, M. R.; Loiselle, D. R.; Daneshvar, M.; Baker-Williams, A. J.; Chisholm, J. D.; Truman, A. W.; Vaughan, C. K.; Haystead, T. A.; Bratslavsky, G.; Bourboulia, D.; Mollapour, M. “Phosphorylation and Ubiquitination Regulate Protein Phosphatase 5 Activity and Its Prosurvival Role in Kidney Cancer.” Cell Reports 2017, 21, 1883-1895. DOI:10.1016/j.celrep.2017.10.074
    • Gumbleton, M.; Sudan, R.; Fernandes, S.; Engelman, R. W.; Russo, C. M.; Chisholm, J. D.; Kerr, W. G. "Dual enhancement of T and NK cell function by pulsatile inhibition of SHIP1 improves antitumor immunity and survival." Sci. Signal. 2017, 10, eaam5353. DOI:10.1126/scisignal.aam5353
    • Adhikari, A. A.; Radal, L.; Chisholm, J. D. "Synthesis of 3,3′-Disubstituted Indolenines Utilizing the Lewis Acid Catalyzed Alkylation of 2,3-Disubstituted Indoles with Trichloroacetimidates." Synlett  2017, 28, 2335-2339. DOI:10.1055/s-0036-1588491
    • Adhikari, A. A.; Suzuki, T.; Gilbert, R. T.; Linaburg, M. R.; Chisholm, J. D. "Rearrangement of Benzylic Trichloroacetimidates to Benzylic Trichloroacetamides." J. Org. Chem. 2017, 82, 3982-3989. 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, 31, 1247-1250. 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, 919-931. DOI: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

    Complete list of publications available on PubMed