Christopher Hulme

Professor, Pharmacology and Toxicology

Professor, BIO5 Institute

Primary Department

Pharmacology and Toxicology

Department Affiliations

Pharmacology and Toxicology

Contact

(520) 626-5322

hulme@arizona.edu

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

Synthesis of kojic acid-derived copper-chelating apoptosis inducing agents

Chen, Y., Lu, P., Hulme, C., & Shaw, A. Y. (2013). Synthesis of kojic acid-derived copper-chelating apoptosis inducing agents. Medicinal Chemistry Research, 22(2), 995-1003.

Abstract:

Three classes of kojic acid derivatives were synthesized and examined for their antiproliferative activity against HeLa cells. Both 8b and 11 co-treated with copper ion exhibited synergistic effect on the HeLa cell growth inhibition with GI50 values of 11.9 and 7.1 μM, respectively. Flow cytometric analysis of HeLa cells revealed that 11-Cu co-treatment induced the sub-G1 arrest in a dose-dependent manner, suggesting that the growth-inhibitory effect is attributed to DNA fragmentation. Moreover, western blot of HeLa cells cytosolic extracts displayed the cleavage of the 116-kDa protein poly(ADP-ribose) polymerase and activation of caspase-3 by the reduced level of the 32-kDa proenzyme, indicating that the caspase-dependent apoptotic pathway was involved. We further demonstrated that MAPK pathway regulators such as ERK and p38 were activated in response to 11-Cu co-treatment, suggesting that the intracellular oxidative stress was dramatically stimulated by the copper ion. Taken together, we have successfully synthesized kojic acid-derived copper-induced apoptotic agents. © 2012 Springer Science+Business Media, LLC.

A novel route to synthesize libraries of quinoxalines via Petasis methodology in two synthetic operations

Hulme, C., Ayaz, M., Dietrich, J., & Hulme, C. -. (2011). A novel route to synthesize libraries of quinoxalines via Petasis methodology in two synthetic operations. Tetrahedron letters, 52(38).

This communication reveals an innovative and facile procedure to prepare quinoxalines in two synthetic steps. The microwave assisted Petasis reaction is followed by the acid mediated unmasking of an internal amino nucleophile, cyclodehydration and oxidation to give collections of quinoxalines in good to excellent yields.

Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE2 production in cells

Hulme, C., Smith, B., Chang, H., Medda, F., Gokhale, V., Dietrich, J., Davis, A., Meuillet, E. J., & Hulme, C. -. (2012). Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE2 production in cells. Bioorganic & medicinal chemistry letters, 22(10).

This Letter presents the synthesis and biological evaluation of a collection of 2-aminothiazoles as a novel class of compounds with the capability to reduce the production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 36 analogs were synthesized and assayed for PGE(2) reduction, and those with potent cellular activity were counter screened for inhibitory activity against COX-2 in a cell free assay. In general, analogs bearing a 4-phenoxyphenyl substituent in the R(2) position were highly active in cells while maintaining negligible COX-2 inhibition. Specifically, compound 5l (R(1)=Me, R(2)=4-OPh-Ph, R(3)=CH(OH)Me) exhibited the most potent cellular PGE(2) reducing activity of the entire series (EC(50)=90 nM) with an IC(50) value for COX-2 inhibition of >5 μM in vitro. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity.

Beyond secretases: Kinase inhibitors for the treatment of Alzheimer's disease

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.

Comments on the use of a dichromophoric circular dichroism assay for the identification of β-turns in peptides

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.

Christopher Hulme