Christopher Hulme

Christopher Hulme

Professor, Pharmacology and Toxicology
Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(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

Medda, F., Smith, B., Gokhale, V., Shaw, A. Y., Dunckley, T., & Hulme, C. (2013). Beyond secretases: Kinase inhibitors for the treatment of Alzheimer's disease. Annual Reports in Medicinal Chemistry, 48, 57-71.

Abstract:

Alzheimer's disease (AD) is the most prevalent form of dementia in old age. Recent data indicate that 24.3 million people worldwide suffer from AD. Hyperphosphorylation of tau, a protein normally involved in microtubule stabilization, has been identified as an important pathological contributor to AD development. In AD brains, hyperphosphorylation of tau leads to its aggregation, misfolding, and formation of neurofibrillary tangles, one common hallmark of AD. Specific protein kinases, such as GSK-3β, CDK5, and DYRK1A, are involved in tau hyperphosphorylation and have been identified as potential targets for the development of novel therapeutic agents for the treatment of AD cognitive deficits. We herein review the current state of the art in the development of small molecule inhibitors of GSK-3β, CDK5, DYRK1A, and other protein kinases involved in tau phosphorylation. Only recently developed compounds with cellular and/or in vivo activity will be discussed. © 2013 Elsevier Inc.

Baldwin, J. E., Claridge, T. D., Hulme, C., Rodger, A., & Schofield, C. J. (1994). Comments on the use of a dichromophoric circular dichroism assay for the identification of β-turns in peptides. International Journal of Peptide and Protein Research, 43(2), 180-184.

PMID: 8200737;Abstract:

Use of the dichromophoric CD assay for β-turn formation in peptide sequences has been investigated. The assay involves the observation of Cotton effects in CD spectra, originating from the approach of N- and C-terminal aromatic chromophores in tetrapeptides. The approach of the chromophores was believed to be brought about by a β-turn in the peptide structure. Our investigations were paralleled by NMR studies which revealed the presence of a previously unreported hydrogen bond in the β-turn conformers, which appears to play a role in the generation of the observed Cotton effects. This suggests caution in the use of the CD technique alone as an assay for β- turn conformers in peptides.

Dömling, A., & Hulme, C. (2011). Molecular Diversity: Editorial. Molecular Diversity, 15(1), 1-2.
Hulme, C., Pinho, L., Martinez-Arisa, G., & Day, K. (2016). Synthesis of Fluorescent Heterocycles via a Knoevenagel/ [4+1]-Cycloaddition Cascade Using Acetyl Cyanide.. Organic and Bio-molecular Chemistry.
Hulme, C., Shaw, A. Y., McLaren, J. A., Nichol, G. S., & Hulme, C. -. (2012). Hydrazine-mediated cyclization of Ugi products to synthesize novel 3-hydroxypyrazoles. Tetrahedron letters, 53(21).

This report discloses a novel concise synthesis of a series of 3-hydroxypyrazoles 5 via a tandem Ugi/debenzylation /hydrazine-mediated cyclization sequence. Herein, n-butyl isocyanide 4b was utilized as an alternative to classical convertible isocyanides enabling high yielding hydrazine-mediated cyclization. Taken together, a novel class of 3-hydroxypyrazoles 5a-5i was synthesized with potential to be of interest in future library enrichment strategies.