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

New multi-component reaction accessing 3-aminoimidazo[1,2-a]pyridines

Schwerkoske, J., Masquelin, T., Perun, T., & Hulme, C. (2005). New multi-component reaction accessing 3-aminoimidazo[1,2-a]pyridines. Tetrahedron Letters, 46(48), 8355-8357.

Abstract:

The novel one step solution phase synthesis of an array of 3-aminoimidazo[1,2-a]pyridines is reported. Reactions were performed in methanol by mixing a α-amino-pyridine, aldehyde and trimethylsilylcyanide (TMSCN) to give the desired product. Mediated by microwave irradiation and catalyzed by scandium triflate, the methodology represents the first one pot preparation of 3-aminoimidazo[1,2-a]pyridines that avoids the use of an isonitrile and subsequent de-protection strategy. The reaction is an example of a formal three-centre-three-component multi-component reaction.

Facile and rapid route for the synthesis of novel norstatine analogs via PADAM-cyclization methodology

Shaw, A. Y., Medda, F., & Hulme, C. (2012). Facile and rapid route for the synthesis of novel norstatine analogs via PADAM-cyclization methodology. Tetrahedron Letters, 53(11), 1313-1315.

Abstract:

The following report describes novel methodology for the rapid synthesis of unique conformationally constrained norstatine analogs of potential biological relevance. A PADAM (Passerini reaction-Amine Deprotection-Acyl Migration reaction) sequence is followed by a TFA-mediated microwave-assisted cyclization to generate the final benzimidazole isostere of the norstatine scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed. © 2012 Elsevier Ltd. All rights reserved.

Concise route to a series of novel 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones

Hulme, C., Gunawan, S., Nichol, G., & Hulme, C. -. (2012). Concise route to a series of novel 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones. Tetrahedron letters, 53(13).

This report presents a novel three step solution phase protocol to synthesize 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones. The strategy utilizes ethyl glyoxalate and mono-N-Boc-protected-o-phenylenediamine derivatives in the Ugi-Azide multi-component reaction (MCR) to generate a unique 1,5-disubstituted tetrazole. Subsequent acid treatment stimulates a simultaneous Boc deprotection and intramolecular cyclization leading to bis-3,4-dihydroquinoxalinone tetrazoles. Direct oxidation using a stable solid-phase radical catalyst (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) with ceric ammonium nitrate (CAN) in catalytic fashion initiating aerobic oxidation, completes the entire procedure to generate a series of original unique bis-quinoxalinone tetrazoles. The method was also expanded to produce a bis-benzodiazepine tetrazole.

Synthesis of a bicyclic γ-lactam dipeptide analogue

Baldwin, J. E., Hulme, C., Edwards, A. J., Schofield, C. J., & Parkes, K. E. (1993). Synthesis of a bicyclic γ-lactam dipeptide analogue. Tetrahedron Letters, 34(10), 1665-1668.

Abstract:

New 4-point pharmacophore method for molecular similarity and diversity applications: Overview of the method and applications, including a novel approach to the design of combinatorial libraries containing privileged substructures

Mason, J. S., Morize, I., Menard, P. R., Cheney, D. L., Hulme, C., & Labaudiniere, R. F. (1999). New 4-point pharmacophore method for molecular similarity and diversity applications: Overview of the method and applications, including a novel approach to the design of combinatorial libraries containing privileged substructures. Journal of Medicinal Chemistry, 42(17), 3251-3264.

PMID: 10464012;Abstract:

A new 4-point pharmacophore method for molecular similarity and diversity that rapidly calculates all potential pharmacophores/pharmacophoric shapes for a molecule or a protein site is described. The method, an extension to the ChemDiverse/Chem-X software (Oxford Molecular, Oxford, England), has also been customized to enable a new internally referenced measure of pharmacophore diversity. The 'privileged' substructure concept for the design of high-affinity ligands is presented, and an example of this new method is described for the design of combinatorial libraries for 7- transmembrane G-protein-coupled receptor targets, where 'privileged' substructures are used as special features to internally reference the pharmacophoric shapes. Up to 7 features and 15 distance ranges are considered, giving up to 350 million potential 4-point 3D pharmacophores/molecule. The resultant pharmacophore 'key' ('fingerprint') serves as a powerful measure for diversity or similarity, calculable for both a ligand and a protein site, and provides a consistent frame of reference for comparing molecules, sets of molecules, and protein sites. Explicit 'on-the- fly' conformational sampling is performed for a molecule to enable the calculation of all geometries accessible for all combinations of four features (i.e., 4-point pharmacophores) at any desired sampling resolution. For a protein site, complementary site points to groups displayed in the site are generated and all combinations of four site points are considered. In this paper we report (i) the details of our customized implementation of the method and its modification to systematically measure 4-point pharmacophores relative to a 'special' substructure of interest present in the molecules under study; (ii) comparisons of 3- and 4-point pharmacophore methods, highlighting the much increased resolution of the 4-point method; (iii) applications of the 4-point potential pharmacophore descriptors as a new measure of molecular similarity and diversity and for the design of focused/biased combinatorial libraries.

Christopher Hulme