Christopher Hulme

Christopher Hulme

Professor, Pharmacology and Toxicology
Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 626-5322

Work Summary

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

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

Moliner, F. D., & Hulme, C. (2012). A Van Leusen deprotection-cyclization strategy as a fast entry into two imidazoquinoxaline families. Tetrahedron Letters, 53(43), 5787-5790.

Abstract:

A concise synthesis of two pharmacologically relevant classes of molecules possessing the imidazoquinoxaline core is reported. The protocol involves use of 1,2-phenylenediamines and glyoxylic acid derivatives, namely ethyl glyoxylate or benzylglyoxamide, along with tosylmethylisocyanides in a microwave-assisted Van Leusen three-component condensation. Subsequent unmasking (Boc removal) of an internal amino-nucleophile promotes deprotection and cyclization that take place either spontaneously in a one-pot fashion to give 8 or upon acidic treatment under microwave irradiation after isolation of the imidazole intermediate to give 11. Of note, a tricyclic framework is hence assembled by means of a rapid and straightforward method with a high bond-forming efficiency. © 2012 Elsevier Ltd. All rights reserved.

Moliner, F. D., & Hulme, C. (2012). Straightforward assembly of phenylimidazoquinoxalines via a one-pot two-step MCR process. Organic Letters, 14(5), 1354-1357.

PMID: 22356134;PMCID: PMC3311158;Abstract:

An efficient multicomponent-based methodology providing a new entry into a medicinally important complex heterocyclic core is presented. The strategy is very general and able to endow target compounds with the highest possible number of diversity points. Notably, four new chemical bonds and two aromatic rings are formed in a one-pot fashion. © 2012 American Chemical Society.

Hulme, C., Moriarty, K., Huang, F., Mason, J., McGarry, D., Labaudiniere, R., Souness, J., & Djuric, S. (1998). Quaternary substituted PDE IV inhibitors II: The synthesis and in vitro evaluation of a novel series of γ-lactams. Bioorganic and Medicinal Chemistry Letters, 8(4), 399-404.

PMID: 9871693;Abstract:

This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE IV) inhibitors. Several of the quaternary substituted lactams presented possess low nanomolar IC50's for PDE IV inhibition.

Vasquez Jr., T. E., Nixey, T., Chenera, B., Gore, V., Bartberger, M. D., Sun, Y., & Hulme, C. (2003). One-pot microwave assisted preparation of pyrazoloquinazolinone libraries. Molecular Diversity, 7(2-4), 161-164.

PMID: 14870845;Abstract:

The novel solution-phase synthesis of an array of biologically relevant pyrazoloquinazolinones in a simple microwave driven one pot procedure is revelaed. Transformations are carried out in good to excellent yield by condensation of α-cyano-ketones and 2-hydrazino-benzoic acids. Subsequent microwave irradiation affords pyrazoloquinazolinones with six points of potential diversification. The protocol described represents a very attractive solution phase procedure for the rapid generation of arrays of such functionalized cores, further demonstrating the growing importance of economic and enabling complexity generating chemistries in the lead discovery arena.

Hulme, C., Peng, J., Louridas, B., Menard, P., Krolikowski, P., & Kumar, N. V. (1998). Applications of N-BOC-diamines for the solution phase synthesis of ketopiperazine libraries utilizing a Ugi/De-BOC/Cyclization (UDC) strategy. Tetrahedron Letters, 39(44), 8047-8050.

Abstract:

This communication reveals a novel application of the 'so-called' convertible isonitrile for the solution phase generation of ketopiperazine libraries. Use of mono N-BOC diamines in the Ugi multi-component reaction (MCR), followed by BOC removal and base treatment (a '3 step, 1-pot procedure') affords ketopiperazines in good yield. The generality of this procedure was further explored revealing novel routes to dihydroquinoxalinones and 1,4-benzodiazepines respectively.