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

The one-pot solution phase preparation of fused tetrazole-ketopiperazines

Nixey, T., Kelly, M., & Hulme, C. (2000). The one-pot solution phase preparation of fused tetrazole-ketopiperazines. Tetrahedron Letters, 41(45), 8729-8733.

Abstract:

A novel application of the TMSN3 modified Ugi 4-component reaction is disclosed for the solution phase synthesis of fused tetrazole-ketopiperazine libraries. The reaction of an aldehyde, primary amine, methyl isocyanoacetate and trimethylsilylazide in methanol at reflux affords bicyclic tetrazole-ketopiperazines in good yield. This efficient one step protocol, producing products with three potential diversity points, may be used to generate arrays of biologically relevant small molecules for general and targeted screening. (C) 2000 Elsevier Science Ltd.

Concise one-pot preparation of unique bis-pyrrolidinone tetrazoles

Gunawan, S., Petit, J., & Hulme, C. (2012). Concise one-pot preparation of unique bis-pyrrolidinone tetrazoles. ACS Combinatorial Science, 14(3), 160-163.

PMID: 22330239;PMCID: PMC3299871;Abstract:

A one-pot, two-step synthesis of bis-pyrrolidinone tetrazoles has been established via the Ugi-Azide reaction using methyl levulinate, primary amines, isocyanides and azidotrimethylsilane with subsequent acid treatment to catalyze the lactam formation. The efficiency of the protocol was established followed by a successful transition to library production in four 24-well plates. © 2012 American Chemical Society.

MCC/S<sub>N</sub>Ar methodology. Part 1: Novel access to a range of heterocyclic cores

Tempest, P., Vu, M. a., Kelly, M. G., Jones, W., & Hulme, C. (2001). MCC/S_NAr methodology. Part 1: Novel access to a range of heterocyclic cores. Tetrahedron Letters, 42(30), 4963-4968.

Abstract:

The novel solution-phase syntheses of arrays of biologically relevant indazolinones, benzazepines and benzoxazepines, utilizing multi-component condensation (MCC)/SNAr methodology is reported. Reaction of commercially available 2-fluoro-5-nitrobenzoic acid with an aldehyde, isonitrile and a primary amine tethered to a Boc-protected internal amino or hydroxyl nucleophile, affords the Ugi product in good yield. Subsequent acid treatment followed by proton scavenging promotes cyclization of internal amino nucleophiles to a variety of ring sizes. Base treatment alone is sufficient to generate benzoxazepines. Interestingly, this communication also introduces a highly efficient two-step route to benzimidazoles. © 2001 Elsevier Science Ltd.

"Multi-component reactions: Emerging chemistry in drug discovery" 'from Xylocain to Crixivan'

Hulme, C., & Gore, V. (2003). "Multi-component reactions: Emerging chemistry in drug discovery" 'from Xylocain to Crixivan'. Current Medicinal Chemistry, 10(1), 51-80.

PMID: 12570721;Abstract:

With the recent emergence of combinatorial chemistry and high-speed parallel synthesis for drug discovery applications, the multi-component reaction (MCR) has seen a resurgence of interest. Easily automated one-pot reactions, such as the Ugi and Passerini reactions, are powerful tools for producing diverse arrays of compounds, often in one step and high yield. Despite this synthetic potential, the Ugi reaction is limited by producing products that are flexible and peptide-like, often being classified as 'non drug-like'. This review details developments of new, highly atom-economic MCR derived chemical methods, which enable the fast and efficient production of chemical libraries comprised of a variety of biologically relevant templates. Representative examples will also be given demonstrating the successful impact of MCR combinatorial methods at different stages of the lead discovery, lead optimization and pre-clinical process development arenas. This will include applications spanning biological tools, natural products and natural product-like diversity, traditional small molecule and 'biotech' therapeutics respectively. In particular, this review will focus on applications of isocyanide based MCR (IMCR) reactions.

Rapid generation of cis-constrained norstatine analogs using a TMSN<sub>3</sub>-modified Passerini MCC/N-capping strategy

Nixey, T., & Hulme, C. (2002). Rapid generation of cis-constrained norstatine analogs using a TMSN₃-modified Passerini MCC/N-capping strategy. Tetrahedron Letters, 43(38), 6833-6835.

Abstract:

A novel application of the TMSN3-modified Passerini three-component reaction is disclosed for the rapid solution phase synthesis of cis constrained norstatine mimetic libraries. The reaction of an N-BOC-α-amino aldehyde, an isocyanide and trimethylsilylazide in dichloromethane, followed by deprotection and N-capping with TFP esters affords cis constrained norstatine mimetics. This efficient protocol, producing products with three diversity points, can be used to generate arrays of biologically relevant small molecules for protease targeted screening. © 2002 Elsevier Science Ltd. All rights reserved.

Christopher Hulme