Christopher Hulme
Professor, BIO5 Institute
Professor, Pharmacology and Toxicology
Primary Department
Department Affiliations
(520) 626-5322
Work Summary
The Hulme group is focused on small molecule drug design and developing enabling chemical methodologies to expedite the drug discovery process. The development of small molecule inhibitors of kinases is of particular interest.
Research Interest
Christopher Hulme, PhD, focuses on small molecule drug design and developing enabling chemical methodologies to expedite the drug discovery process. Target families of particular current interest for the group are kinases, protein-protein interactions and emerging DNA receptors for indications in oncology. Such efforts are highly collaborative in nature and students will be exposed to the full array of design hurdles involved in progressing molecules along the value chain to clinical evaluation. These efforts will be aided by the group’s interest in both microwave assisted organic synthesis (MAOS) and flow chemistry. Both technologies enable ‘High-throughput Medicinal Chemistry’ (HTMC) and will be supported by similar High-throughput Purification capabilities.The group also has a long standing interest in the development of new reactions that produce biologically relevant molecules in an efficient manner. Front loading screening collections with molecules possessing high ‘iterative efficiency potential’ is critical for expediting the drug discovery process. The discovery of such tools that perturb cellular systems is of high value to the scientific community and may be facilitated by rapid forays into MCR space that can produce a multitude of novel scaffolds with appropriate decoration for evaluation with a variety of different screening paradigms.Novel hypervalent iodine mediated C-H activation methodologies is also an active area of interest. Probing the scope of the transformation below and investigating applications toward the synthesis of new peptidomimetics will be an additional pursuit in the Hulme group.

Publications

Hulme, C., Shaw, A. Y., Denning, C. R., & Hulme, C. -. (2012). Selenium dioxide-mediated synthesis of α-ketoamides from arylglyoxals and secondary amines. Tetrahedron letters, 53(32).

A facile and expeditious synthetic approach to α-ketoamides 3 is described. A series of α-ketoamides 3 was synthesized via reaction of selenium dioxide-mediated oxidative amidation between arylglyoxals 1 and secondary amines 2, and accelerated with microwave irradiation. Our findings indicate that constrained amines, such as piperazine and piperidine exhibit higher conversions for this transformation. This reaction was explored by synthesizing a series of α-ketoamides 3 from various arylglyoxals with cyclic and acyclic secondary amines.

Hsu, M., Dietrich, J., Hulme, C., & Shaw, A. Y. (2013). Synthesis of di- and tri-substituted imidazole-4-carboxylates via PBu3-mediated [3+2] cycloaddition. Synthetic Communications, 43(11), 1538-1542.

Abstract:

Some new di- and trisubstituted imidazole-4-carboxylates were prepared from amidoacetic acids 3 in the present report. The key step to establish such imidazole- 4-carboxylates stemmed from the PBu3-mediated [3+2] cycloaddition between in situ-generated Δ2-oxazolinone 4 and ethyl cyanoformate6. Our results indicated that trisubstituted imidazoles 7-20 were afforded in better yields than those of disubstituted imidazoles 21-27. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications1 to view the free supplemental file. Copyright © Taylor & Francis Group, LLC.

Kusne, Y., Carrera-Silva, E. A., Perry, A. S., Rushing, E. J., Mandell, E. K., Dietrich, J. D., Errasti, A. E., Gibbs, D., Berens, M. E., Loftus, J. C., Hulme, C., Yang, W., Lu, Z., Aldape, K., Sanai, N., Rothlin, C. V., & Ghosh, S. (2014). Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFα in glioblastoma. Science signaling, 7(338), ra75.

Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-α (TNFα) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFα-dependent activation of the transcription factor nuclear factor κB (NF-κB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy.

Masquelin, T., Bui, H., Brickley, B., Stephenson, G., Schwerkoske, J., & Hulme, C. (2006). Sequential Ugi/Strecker reactions via microwave assisted organic synthesis: Novel 3-center-4-component and 3-center-5-component multi-component reactions. Tetrahedron Letters, 47(17), 2989-2991.

Abstract:

Two novel one-step microwave mediated syntheses of arrays of 3-iminoaryl-imidazo[1,2-a]pyridines and imidazo[1,2-a]pyridyn-3-ylamino-2- acetonitriles are reported. Reactions are performed under microwave condition in methanol by simply mixing α-amino-pyridines, aldehydes, and trimethylsilylcyanide (TMSCN) with distinct reagent stoichiometries, catalyzed by polymer-bound scandium triflate, to afford either product. Furthermore, functionally different aldehydes were shown to proceed to different end-points, adding an extra caveat to the studies. The new methodology represents examples of both formal 3-center-4-component and 3-center-5-component multi-component reactions. © 2006 Elsevier Ltd. All rights reserved.

Zhigang, X. u., Shaw, A. Y., Nichol, G. S., Cappelli, A. P., & Hulme, C. (2012). Applications of ortho-phenylisonitrile and ortho-N-Boc aniline for the two-step preparation of novel bis-heterocyclic chemotypes. Molecular Diversity, 16(3), 607-612.

PMID: 22622389;Abstract:

Concise routes to five pharmacologically relevant bis-heterocyclic scaffolds are described. Significant molecular complexity is generated in a mere two synthetic operations enabling access to each scaffold. Routes are often improved by microwave irradiation and all utilize isocyanide-based multi-component reaction methods to incorporate the required diversity elements. Common reagents in all initial condensation reactions include 2-(N-Boc-amino)-phenyl-isocyanide 1, mono-Boc-phenylenediamine 2 and ethyl glyoxalate 3. © Springer Science+Business Media B.V. 2012.