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

Novel applications of ethyl glyoxalate with the Ugi MCR

Hulme, C., & Cherrier, M. -. (1999). Novel applications of ethyl glyoxalate with the Ugi MCR. Tetrahedron Letters, 40(29), 5295-5299.

Abstract:

This letter describes novel high-yielding solution phase preparations of 1,4-benzodiazepine-2,5-dione, diketopiperazine, ketopiperazine and dihydroquinoxalinone libraries via a UDC (Ugi/de-Boc/cyclization) strategy in combination with ethylglyoxalate. The methodology represents a 'three step, one-pot procedure', employing the Ugi multi-component reaction (MCR), followed by Boc deprotection and cyclization.

Solid-phase synthesis and structure-activity relationships of novel biarylethers as melanin-concentrating hormone receptor-1 antagonists

Vu, M. a., Bannon, A. W., Baumgartner, J., Hale, C., Hsieh, F., Hulme, C., Rorrer, K., Salon, J., Staden, C. v., & Tempest, P. (2006). Solid-phase synthesis and structure-activity relationships of novel biarylethers as melanin-concentrating hormone receptor-1 antagonists. Bioorganic and Medicinal Chemistry Letters, 16(19), 5066-5072.

PMID: 16887348;Abstract:

Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic neuropeptide. The action of MCH on feeding is thought to involve the activation of its respective G protein-coupled receptor MCH-R1. Consequently, antagonists that block MCH regulated MCH-R1 activity may provide a viable approach to the treatment of diet-induced obesity. This communication reports the discovery of a novel MCH-R1 receptor antagonist, the biarylether 7, identified through high throughput screening. The solid-phase synthesis and structure-activity relationship of related analogs is described. © 2006 Elsevier Ltd. All rights reserved.

Inhibitors of tyrosine kinases involved in inflammation and autoimmune disease

Myers, M. R., Wei, H. e., & Hulme, C. (1997). Inhibitors of tyrosine kinases involved in inflammation and autoimmune disease. Current Pharmaceutical Design, 3(5), 473-502.

Abstract:

The study of tyrosine kinases involved in cellular signaling associated with inflammation and autoimmune disease is rapidly progressing. Lessons learned from recent successes in identifying novel, potent, and selective tyrosine kinase inhibitors for the treatment of cancer and cardiovascular disease can be applied toward developing selective tyrosine kinase inhibitors for targets associated with diseases such as rheumatoid arthritis, sepsis and autoimmune disease. The design of new selective tyrosine kinase inhibitors will be aided by the very recent successes in solving X-ray crystal structures of the catalytic domains of several kinases. This paper summarizes the literature on inhibitors of several non-receptor and receptor tyrosine kinases thought to be involved in cellular signaling associated with inflammatory diseases.

3-(4-Bromophenyl)-1-butyl-5-[1-(2-chloro-6-methylphenyl)-1H-tetrazol-5-yl] imidazolidine-2,4-dione

Hall, G. B., Medda, F., Roberts, S. A., & Hulme, C. (2013). 3-(4-Bromophenyl)-1-butyl-5-[1-(2-chloro-6-methylphenyl)-1H-tetrazol-5-yl] imidazolidine-2,4-dione. Acta Crystallographica Section E: Structure Reports Online, 69(7), o1102-o1103.

PMID: 24046663;PMCID: PMC3770378;Abstract:

In the title molecule, C21H20BrClN6O2, the chloro-substituted benzene ring forms a dihedral angle of 77.84 (7)° with the tetrazole ring and the bromo-substituted ring forms a dihedral angle of 43.95 (6)° with the imidazole ring. The dihedral angle between the tetrazole and imidazole rings is 67.42 (8)°. The terminal methyl group of the butyl substituent is disordered over two sets of sites, with refined occupancies 0.67 (3) and 0.33 (3). In the crystal, there is a short Br...N contact of 3.183 (2) Å.

Applications of Isocyanides in IMCRs for the Rapid Generation of Molecular Diversity

Ayaz, M., Moliner, F. D., Dietrich, J., & Hulme, C. (2012). Applications of Isocyanides in IMCRs for the Rapid Generation of Molecular Diversity. Isocyanide Chemistry: Applications in Synthesis and Material Science, 335-384.

Christopher Hulme