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

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.

Tempest, P., Vu, M. a., Kelly, M. G., Jones, W., & Hulme, C. (2001). MCC/SNAr 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.

Salamant, W., & Hulme, C. (2006). Unique one step, multicomponent α,β,β-oxidations of carbamates with Willgerodt-like hypervalent iodine reagents - An example of triple C-H bond activation. Tetrahedron Letters, 47(4), 605-609.

Abstract:

This communication reveals a novel multicomponent oxidation of saturated, urethane protected nitrogen heterocyclic systems. The oxidation is facile, general, high yielding and involves the application of readily-made hypervalent iodine reagents, giving an α,β,β-oxidation pattern relative to the nitrogen of the heterocycle. The oxidation is multicomponent type III, in that the substrate, reagent and solvent provide the three inputs during the reaction. The transformation also represents an example of triple C-H bond activation. A mechanistic rationale for this is proposed. © 2005 Elsevier Ltd. All rights reserved.

Smith, B., Medda, F., Gokhale, V., Dunckley, T., & Hulme, C. (2012). Recent advances in the design, synthesis, and biological evaluation of selective DYRK1A inhibitors: A new avenue for a disease modifying treatment of Alzheimers?. ACS Chemical Neuroscience, 3(11), 857-872.

PMID: 23173067;PMCID: PMC3503344;Abstract:

With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimers disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimers disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimers disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors. © 2012 American Chemical Society.

Martinez-Ariza, G., Ayaz, M., & Hulme, C. (2013). A simple one-pot 2-step N-1-alkylation of indoles with α-iminoketones toward the expeditious 3-step synthesis of N-1-quinoxaline-indoles. Tetrahedron Letters, 54(49), 6719-6721.

Abstract:

A straightforward procedure for the preparation of N-quinoxaline-indoles is presented. A base-catalyzed one-pot addition of indoles to a preformed α-iminoketone proceeds on the N-1 indole and the subsequent adduct undergoes an acid-mediated deprotection of an internal amino nucleophile, intramolecular cyclization, and final oxidation generating N-1-quinoxaline- indoles in good yield. © 2013 Elsevier Ltd. All rights reserved.