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

Two-step syntheses of fused quinoxaline-benzodiazepines and bis-benzodiazepines

Zhigang, X. u., Dietrich, J., Shaw, A. Y., & Hulme, C. (2010). Two-step syntheses of fused quinoxaline-benzodiazepines and bis-benzodiazepines. Tetrahedron Letters, 51(34), 4566-4569.

Abstract:

A two-step solution phase synthesis employing a double UDC (Ugi/Deprotect/Cyclize) strategy has been utilized to obtain fused 6,7,6,6-quinoxalinone-benzodiazepines and 6,7,7,6-bis-benzodiazepines. Optimization of the methodology to produce these tetracyclic scaffolds was enabled by microwave irradiation, incorporation of trifluoroethanol as solvent, and the use of the convertible isocyanide, 4-tert-butyl cyclohexen-1-yl isocyanide.

General one-pot, two-step protocol accessing a range of novel polycyclic heterocycles with high skeletal diversity

Hulme, C., Xu, Z., Ayaz, M., Cappelli, A. A., & Hulme, C. -. (2012). General one-pot, two-step protocol accessing a range of novel polycyclic heterocycles with high skeletal diversity. ACS combinatorial science, 14(8).

An Ugi one-pot three-component four-center reaction was coupled with a subsequent acid mediated cyclodehydration step to furnish a multitude of unique scaffolds having in common an embedded or attached benzimidazole and often a ring system formed through lactamization. Using combinations of tethered Ugi inputs typically via tethered acid-ketone inputs and supporting reagents containing masked internal nucleophiles, such scaffolds were produced in good to excellent yields in an operationally friendly manner.

Crystal structures of N-tert-butyl-3-(4-fluoro-phenyl)-5-oxo-4-[2-(tri-fluoro-meth-oxy)phen-yl]-2,5-di-hydro-furan-2-carboxamide and 4-(2H-1,3-benzodioxol-5-yl)-N-cyclo-hexyl-5-oxo-3-[4-(tri-fluoro-meth-yl)phen-yl]-2,5-di-hydro-furan-2-carboxamide

Roberts, S. A., Martinez-Ariza, G., & Hulme, C. (2015). Crystal structures of N-tert-butyl-3-(4-fluoro-phenyl)-5-oxo-4-[2-(tri-fluoro-meth-oxy)phen-yl]-2,5-di-hydro-furan-2-carboxamide and 4-(2H-1,3-benzodioxol-5-yl)-N-cyclo-hexyl-5-oxo-3-[4-(tri-fluoro-meth-yl)phen-yl]-2,5-di-hydro-furan-2-carboxamide. Acta crystallographica. Section E, Crystallographic communications, 71(Pt 2), 199-202.

The title compounds, C22H19F4NO4, (I), and C25H22F3NO5, (II), each contain a central nearly planar di-hydro-furan-one ring. The r.m.s. deviation from planarity of these rings is 0.015 Å in (I) and 0.027 Å in (II). The mol-ecules are T-shaped, with the major conformational difference being the O-C-C-O torsion angle [-178.9 (1) in (I) and 37.7 (2)° in (II)]. In the crystal of (I), mol-ecules are linked by N-H⋯O hydrogen bonds, forming chains along [001] while in (II) mol-ecules are linked by N-H⋯O hydrogen bonds, forming chains along [010]. In (II), the tri-fluoro-methyl substituent is disordered over two sets of sites, with refined occupancies of 0.751 (3) and 0.249 (3).

Concise Two-Step Solution Phase Syntheses of four novel Dihydroquinazoline scaffolds

Hulme, C., Dietrich, J., Kaiser, C., Meurice, N., & Hulme, C. -. (2010). Concise Two-Step Solution Phase Syntheses of four novel Dihydroquinazoline scaffolds. Tetrahedron letters, 51(30).

Novel two-step solution phase protocols for the synthesis of dihydroquinazolines and fused dihydroquinazoline-benzodiazepine tetracycles are reported. The methodology employs the Ugi reaction to assemble desired diversity and acid treatment enables ring closing transformations. The protocols are further facilitated by the use of microwave irradiation and n-butyl isocyanide to control the rate of each ring forming transformation.

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

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

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.

Christopher Hulme