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

A simple, cheap alternative to 'designer convertible isonitriles' expedited with microwaves

Hulme, C., Chappeta, S., & Dietrich, J. (2009). A simple, cheap alternative to 'designer convertible isonitriles' expedited with microwaves. Tetrahedron Letters, 50(28), 4054-4057.

Abstract:

Interest in designer convertible isonitriles has increased in recent years with the growing recognition that isonitrile-based multi-component reactions (IMCRs) are highly effective in rapidly accessing, new and pharmacologically relevant diversity space. This Letter reports on the novel use of n-butylisonitrile as a cheaper and more atom-economical alternative to currently reported 'designer convertible isonitriles', facilitated by the advent of microwave-assisted organic synthesis (MAOS).

(Z)-Stereoselective Synthesis of Mono- and Bis-heterocyclic Benzimidazol-2-ones via Cascade Processes Coupled with the Ugi Multicomponent Reaction

Xu, Z., Martinez-Ariza, G., Cappelli, A. P., Roberts, S. A., & Hulme, C. (2015). (Z)-Stereoselective Synthesis of Mono- and Bis-heterocyclic Benzimidazol-2-ones via Cascade Processes Coupled with the Ugi Multicomponent Reaction. The Journal of organic chemistry, 80(18), 9007-15.

Several novel cascade reactions are herein reported that enable access to a variety of unique mono- and bis-heterocyclic scaffolds. The sequence of cascade events are mediated through acid treatment of an Ugi adduct that affords 1,5-benzodiazepines which subsequently undergo an elegant rearrangement to deliver (E)-benzimidazolones, which through acid-promoted tautomerization convert to their corresponding (Z)-isomers. Moreover, a variety of heterocycles tethered to (Z)-benzimidazole-2-ones are also accessible through similar domino-like processes, demonstrating a general strategy to access significantly new scaffold diversity, each containing four points of potential diversification. Final structures of five scaffolds have been definitively proven by X-ray crystallography.

α-Azidonation of amides, carbamates, and ureas with the iodosylbenzene/trimethylsilyl azide reagent combination: N-acyliminium ion precursors

Magnus, P., Hulme, C., & Weber, W. (1994). α-Azidonation of amides, carbamates, and ureas with the iodosylbenzene/trimethylsilyl azide reagent combination: N-acyliminium ion precursors. Journal of the American Chemical Society, 116(10), 4501-4502.

Remarkable three-step-one-pot solution phase preparation of novel imidazolines utilizing a UDC (Ugi/de-Boc/cyclize) strategy

Hulme, C., Liang, M. a., Romano, J., & Morrissette, M. (1999). Remarkable three-step-one-pot solution phase preparation of novel imidazolines utilizing a UDC (Ugi/de-Boc/cyclize) strategy. Tetrahedron Letters, 40(45), 7925-7928.

Abstract:

This communication reveals the novel solution phase synthesis of an array of biologically relevant imidazolines in a remarkable 'three-step-one-pot' procedure, utilizing a Ugi/de-Boc/cyclization (UDC) strategy. Transformations are carried out in excellent yield by condensation of N-Boc-α-amino-aldehydes and supporting Ugi reagents. The described protocol represents a highly attractive solution phase procedure for the rapid generation of this class of molecule.

Emerging molecular diversity from the intra-molecular Ugi reaction: Iterative efficiency in medicinal chemistry

Hulme, C., & Dietrich, J. (2009). Emerging molecular diversity from the intra-molecular Ugi reaction: Iterative efficiency in medicinal chemistry. Molecular Diversity, 13(2), 195-207.

PMID: 19205916;Abstract:

This review details a now established area within the isonitrile multi-component reaction (IMCR) field of study, namely employing bi-functional reagents in the Ugi reaction for the construction of screening sets with the additional element or even possibly 'metric' of enhanced 'iterative efficiency potential'. The concept of 'iterative efficiency' will be briefly introduced, coupled with discussion on new synthetic routes to select bi-functional IMCR precursors and their use in the generation of pharmacologically relevant 'molecular diversity'. © 2009 Springer Science+Business Media B.V.

Christopher Hulme