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 Tetrazolo-Fused Benzodiazepines and Benzodiazepinones by a Two-Step Protocol Using an Ugi-Azide Reaction for Initial Diversity Generation

Hulme, C., Gunawan, S., Ayaz, M., De Moliner, F., Frett, B., Kaiser, C., Patrick, N., Xu, Z., & Hulme, C. -. (2012). Synthesis of Tetrazolo-Fused Benzodiazepines and Benzodiazepinones by a Two-Step Protocol Using an Ugi-Azide Reaction for Initial Diversity Generation. Tetrahedron, 68(27-28).

A two-step strategy for the synthesis of arrays of tricyclic tetrazolo-fused benzodiazepines and benzodiazepinones has been investigated. The protocol uses ortho-N-Boc phenylisocyanides and phenylglyoxaldehydes or ethyl glyoxylate in the 4-component Ugi-Azide reaction to afford MCR (Multi Component Reactions) derived adducts equipped with the desired diversity inputs. A subsequent acidic treatment (TFA/DCE) allows a simultaneous deprotection-cyclization leading to the final products.

Emerging approaches for the syntheses of bicyclic imidazo[1,2-x]- heterocycles

Hulme, C., & Lee, Y. (2008). Emerging approaches for the syntheses of bicyclic imidazo[1,2-x]- heterocycles. Molecular Diversity, 12(1), 1-15.

PMID: 18409015;Abstract:

Imidazo-[1,2-x]heterocycles are versatile building blocks for use in both a 'drug hunters' quest to discover new leads and a chemical biologists search for effective molecular tools in 'cell perturbation' studies. At the front end of the drug discovery flow chart, the last 5-10 years have witnessed the discovery of new high-throughput methodologies which very quickly have enabled access to virtual libraries of these chemo-types in the realm of 10⁷ derivatives. Interestingly, these often neglected cores in patent cooperation treaty (PCT) applications appear in several highly effective marketed drugs, completing the medicinal chemists search for clinical success. Such rigid chemo-types, all containing a bridgehead nitrogen atom, are thus poised for an ever increasing impact on the discovery and development of new molecular therapeutics. The following mini-review will briefly cover therapeutic utility, chemical methodologies and automation developed to enable preparation of arrays of these chemo-types in a high-throughput manner. Synthetic emphasis is placed on a 3-component-3-center isocyanide based multi-component reaction (IMCR), which spans solution, solid phase, flourous and microwave assisted organic synthesis. © 2008 Springer Science+Business Media B.V.

Novel applications of convertible isonitriles for the synthesis of mono and bicyclic γ-lactams via a UDC strategy

Hulme, C., Liang, M. a., Cherrier, M., Romano, J. J., Morton, G., Duquenne, C., Salvino, J., & Labaudiniere, R. (2000). Novel applications of convertible isonitriles for the synthesis of mono and bicyclic γ-lactams via a UDC strategy. Tetrahedron Letters, 41(12), 1883-1887.

Abstract:

This communication reveals a novel application of the so-called convertible isonitriles for the solution/solid phase generation of γ-lactam analogues. Use of tethered N-BOC aldehydes in the Ugi multi-component reaction (MCR), followed by BOC removal and base treatment (a '3-step, 1-pot procedure') affords γ-lactams in good yield. The UDC (Ugi/De-BOC/Cyclize) strategy, coupled with a convertible isonitrile, is now feasible from all three substitution sites of the Ugi product. A conceptually novel approach, combining a bi-functional precursor with a post-condensation modification to give fused lactam-ketopiperazines, is also revealed. (C) 2000 Elsevier Science Ltd.

Synthesis of peptidomimetics, δ- And ε-lactam tetrazoles

Gunawan, S., Keck, K., Laetsch, A., & Hulme, C. (2012). Synthesis of peptidomimetics, δ- And ε-lactam tetrazoles. Molecular Diversity, 16(3), 601-606.

PMID: 22622388;Abstract:

A concise two-step procedure for the synthesis of novel δ-lactam tetrazoles has been established via the Ugi-azide reaction using 5-oxohexanoic acid along with primary amines, isocyanides, and azidotrimethylsilane followed by 1,1′-carbonyldiimidazole-mediated intramolecular amide formation. Expansion to ε-lactam tetrazole scaffolds was accomplished using methyl 6-oxoheptanoate via the same Ugi-azide reaction followed by basic hydrolysis and SOCl2 activation to enable lactam formation. © Springer Science+Business Media B.V. 2012.

Novel applications of resin bound α-amino acids for the synthesis of benzodiazepines (via Wang resin) and ketopiperazines (via hydroxymethyl resin)

Hulme, C., Liang, M. a., Kumar, N. V., Krolikowski, P. H., Allen, A. C., & Labaudiniere, R. (2000). Novel applications of resin bound α-amino acids for the synthesis of benzodiazepines (via Wang resin) and ketopiperazines (via hydroxymethyl resin). Tetrahedron Letters, 41(10), 1509-1514.

Abstract:

This communication reveals a novel application of resin bound α-amino acids coupled with the UDC (Ugi/DeBOC/cyclize) strategy. Reaction with either N-BOC-α-amino aldehydes or N-BOC anthranilic acids and subsequent acid treatment allows the preparation of highly pure and diverse arrays (approx. 10000 in size) of 1,4-benzodiazepines (Wang resin) and ketopiperazines (hydroxymethyl resin), respectively. Notable for the benzodiazepine series of compounds are the five potential points of diversity available from this two-step protocol. (C) 2000 Elsevier Science Ltd.

Christopher Hulme