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

Novel safety-catch linker and its application with a Ugi/De- BOC/cyclization (UDC) strategy to access carboxylic acids, 1,4- benzodiazepines, diketopiperazines, ketopiperazines and dihydroquinoxalinones

Hulme, C., Peng, J., Morton, G., Salvino, J. M., Herpin, T., & Labaudiniere, R. (1998). Novel safety-catch linker and its application with a Ugi/De- BOC/cyclization (UDC) strategy to access carboxylic acids, 1,4- benzodiazepines, diketopiperazines, ketopiperazines and dihydroquinoxalinones. Tetrahedron Letters, 39(40), 7227-7230.

Abstract:

This communication reveals the synthesis and application of a novel resin bound isonitrile. The resin is an example of a novel safety-catch linker which upon BOC-activation can be resin cleaved with a variety of nucleophiles. Use of this polymer supported isonitrile in the Ugi multi- component reaction (MCR), followed by resin clipping and cyclization allows access to diverse arrays of 1,4-benzodiazepine-2,5-diones, diketopiperazines and ketopiperazines respectively. The methoxide safety-catch clipping strategy and subsequent solution phase cyclization offers similar advantages to a traceless linker.

Short solution phase preparation of fused azepine-tetrazoles via a UDC (Ugi/de-Boc/cyclize) strategy

Nixey, T., Kelly, M., Semin, D., & Hulme, C. (2002). Short solution phase preparation of fused azepine-tetrazoles via a UDC (Ugi/de-Boc/cyclize) strategy. Tetrahedron Letters, 43(20), 3681-3684.

Abstract:

A novel application of the TMSN3 modified Ugi 4-component reaction is disclosed for the solution phase synthesis of fused azepine-tetrazole libraries. The reaction of a N-Boc-α-amino aldehyde, secondary amine, methyl isocyanoacetate and trimethylsilylazide in methanol, followed by acid treatment, proton scavenging and reflux affords bicyclic azepine-tetrazoles. This efficient protocol, producing products with three diversity points, can be used to generate arrays of biologically relevant small molecules for general and targeted screening. © 2002 Elsevier Science Ltd. All rights reserved.

2-Butyl-11-phenyl-5,10-dihydro-1H-benzo[e]imidazo[1,5-a][1,4]diazepine-1, 3(2H)-dione

Nichol, G. S., Gunawan, S., Dietrich, J., & Hulme, C. (2010). 2-Butyl-11-phenyl-5,10-dihydro-1H-benzo[e]imidazo[1,5-a][1,4]diazepine-1, 3(2H)-dione. Acta Crystallographica Section E: Structure Reports Online, 66(3), o625.

PMID: 21580382;PMCID: PMC2983587;Abstract:

The title compound, C21H21N3O2, was obtained following a five-step synthetic procedure yielding weakly diffracting rod and needle-shaped crystals which crystallized concomitantly. Structural analysis of a rod-shaped crystal showed that the central seven-membered heterocyclic ring adopts a conformation that is perhaps best described as a distorted boat, with the H-bearing (CH2 and NH) atoms lying well out of the least-squares mean plane fitted through the other five atoms in the ring (r.m.s. deviation 0.075 Å). In the crystal, the compound packs as a twisted chain, which propagates along the b axis by means of an R ¹2(6) motif formed by one of the carbonyl O atoms acting as a bifurcated acceptor in an N - H⋯O and C - H⋯O inter-action. No diffraction was observed from the needle-shaped crystals.

4-(piperidin-1-yl)-4H-benzo[b]tetrazolo-[1,5-d][1,4]diazepin-5(6H)-one

Nichol, G. S., Zhigang, X. u., Kaiser, C. E., & Hulme, C. (2011). 4-(piperidin-1-yl)-4H-benzo[b]tetrazolo-[1,5-d][1,4]diazepin-5(6H)-one. Acta Crystallographica Section E: Structure Reports Online, 67(1), o23-o24.

PMID: 21522729;PMCID: PMC3050344;Abstract:

There are two crystallographically unique molecules present in the asymmetric unit of the title compound, C14H16N 6O; in both molecules, the seven-membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each molecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between molecule A and symmetry equivalents forms two ring motifs, the first formed by inversion-related n-h ⋯ o interactions and the second formed by c-h ⋯ o and c-h⋯n interactions. The combination of both ring motifs results in the formation of an infinite double tape, which propagates in the a-axis direction. hydrogen bonding between molecule B and symmetry equivalents forms one ring motif by inversion-related n-h ⋯ o interactions and a second ring motif by c-h ⋯ o interactions, which propagate as a single tape parallel with the c axis.

Applications of Multicomponent Reactions in Drug Discovery - Lead Generation to Process Development

Hulme, C. (2005). Applications of Multicomponent Reactions in Drug Discovery - Lead Generation to Process Development. Multicomponent Reactions, 311-341.

Christopher Hulme