Christopher Hulme

Christopher Hulme

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

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

Martinez-Ariza, G., Dietrich, J., Moliner, F. D., & Hulme, C. (2013). A tandem [3+2] cycloaddition-elimination cascade reaction to generate pyrrolo-[3,4-c]pyrrole-1,3-diones. Synlett, 24(14), 1801-1804.

Abstract:

An efficient tandem [3+2] cycloaddition-elimination cascade sequence has been developed enabling assembly of the pharmacologically relevant pyrrolo-[3,4-c]pyrrole-1,3-dione chemotype. The strategy involves simple mixing of readily accessible oxazolin-2-ones and pyrrole-2,5-diones in the presence of base under mild conditions, rendering the title compounds in typically excellent yields. Of note, this route allows for installation of three points of diversity and is ideal for combinatorial applications and parallel synthesis production campaigns. © Georg Thieme Verlag Stuttgart · New York.

Hulme, C., Xu, Z., Shaw, A. Y., Dietrich, J., Cappelli, A. P., Nichol, G., & Hulme, C. -. (2012). Facile, novel two-step syntheses of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines. Molecular diversity, 16(1).

Three scaffolds of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines were synthesized via Ugi/de-protection/cyclization methodology. Benzimidazole forming ring closure was enabled under microwave irradiation in the presence of 10% TFA/DCE. The methodology demonstrates the utility of 2-(N-Boc-amino)-phenyl-isocyanide for the generation of new molecular diversity.

Umkehrer, M., Ross, G., Jäger, N., Burdack, C., Kolb, J., Hong, H. u., Alvim-Gaston, M., & Hulme, C. (2007). Expeditious synthesis of imidazo[1,2-c]pyrimidines via a [4+1]-cycloaddition. Tetrahedron Letters, 48(12), 2213-2216.

Abstract:

A new and versatile synthesis of imidazo[1,2-c]pyrimidines via a [4+1]-cycloaddition is described. The reported novel synthetic approach leads to pharmacologically interesting scaffolds containing three points of potential diversity, which previously were not accessible under conventional conditions. In addition, this novel synthetic procedure is amenable to the assembly of libraries with this interesting core structure. © 2007 Elsevier Ltd. All rights reserved.

Viswanadhan, V. N., Balan, C., Hulme, C., Cheetham, J. C., & Sun, Y. (2002). Knowledge-based approaches in the design and selection of compound libraries for drug discovery. Current Opinion in Drug Discovery and Development, 5(3), 400-406.

PMID: 12058615;Abstract:

In the past decade, the pharmaceutical industry has realized the increasing significance of impacting the early phase hit-to-lead development in the drug discovery process. In particular, knowledge-based approaches emerged and evolved to address a multitude of issues such as absorption, distribution, metabolism and excretion (ADME), potency, toxicity and overall drugability. Each of these approaches seeks to bring together all relevant pieces of information and create a knowledge-oriented process to deploy such information in drug discovery. This review focuses on work relating to drugability, which aims at obtaining hits (or leads) that have enhanced likelihoods of leading to successful clinical candidates by medicinal chemistry efforts. The period covered in this review is from 1997 (since the publication of Lipinski's rule of 5) to March 2002.

Hulme, C., Poli, G. B., Huang, F., Souness, J. E., & Djuric, S. W. (1998). Quaternary substituted PDE4 inhibitors I: The synthesis and in vitro evaluation of a novel series of oxindoles. Bioorganic and Medicinal Chemistry Letters, 8(2), 175-178.

PMID: 9871649;Abstract:

The following letter presents the synthesis and in vitro evaluation of a novel quaternary substituted series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds represent conformationally constrained analogues of the Celltech PDE IV inhibitor, CDP 840. Examples with sub-micromolar IC50's for PDE4 inhibition are reported.