Christopher Hulme
Professor, BIO5 Institute
Professor, Pharmacology and Toxicology
Primary Department
Department Affiliations
(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

Bell, C. E., Shaw, A. Y., Moliner, F. D., & Hulme, C. (2014). MCRs reshaped into a switchable microwave-assisted protocol toward 5-aminoimidazoles and dihydrotriazines. Tetrahedron, 70(1), 54-59.

Abstract:

A tunable microwave-assisted protocol for the synthesis of two biologically relevant families of heterocycles has been designed. Via a simple switch of reaction conditions, the same starting materials can be engaged in either an improved synthesis of the dihydrotriazine scaffold or a novel, first-in-class MCR to render the challenging 5-aminoimidazole nucleus in a single step. An additional first-in-class MCR is also reported utilizing guanidines to afford 2,5-aminoimidazoles. © 2013 Elsevier Ltd. All rights reserved.

Zhigang, X. u., Moliner, F. D., Cappelli, A. P., Ayaz, M., & Hulme, C. (2014). Expeditious routes to polycyclic molecular frameworks via one-pot, two-step Ugi ring-closing sequences. Synlett, 25(2), 225-228.

Abstract:

A very general and robust multicomponent-reaction protocol involving an Ugi condensation between ethyl glyoxylate, isonitriles, N-Boc-α-amino acids, and mono-N-Boc-protected diamines followed by a series of acid-promoted cyclization steps in a one-pot fashion is reported. This process allows for the assembly of complex polycyclic structures by means of just two simple synthetic operations and a single chromatographic purification in high overall yields. Of note, the first scaffolds derived from a highly Âselective sequence of ring-closing events involving three internal amino nucleophiles is reported. © Georg Thieme Verlag Stuttgart New York.

Martinez-Ariza, G., & Hulme, C. (2015). Recent advances in allosteric androgen receptor inhibitors for the potential treatment of castration-resistant prostate cancer. Pharmaceutical patent analyst, 4(5), 387-402.

Prostate cancer (PC) is the second most frequent cause of male cancer death in the USA. As such, the androgen receptor (AR) plays a crucial role in PC, making AR the major therapeutic target for PC. Current antiandrogen chemotherapy prevents androgen binding to the ligand-binding pocket (LBP) of AR. However, PC frequently recurs despite treatment and it progresses to castration-resistant prostate cancer. Behind this regression is renewed AR signaling initiated via mutations in the LBP. Hence, there is a critical need to improve the therapeutic options to regulate AR activity in sites other than the LBP. Herein, recently disclosed (2010-2015) allosteric AR inhibitors are summarized and a perspective on the potential pharmaceutical intervention at these sites is provided.

Martinez-Ariza, G., Ayaz, M., Roberts, S. A., Rabanal-León, W. A., Arratia-Pérez, R., & Hulme, C. (2015). The Synthesis of Stable, Complex Organocesium Tetramic Acids through the Ugi Reaction and Cesium-Carbonate-Promoted Cascades. Angewandte Chemie (International ed. in English), 54(40), 11672-6.

Two structurally unique organocesium carbanionic tetramic acids have been synthesized through expeditious and novel cascade reactions of strategically functionalized Ugi skeletons delivering products with two points of potential diversification. This is the first report of the use of multicomponent reactions and subsequent cascades to access complex, unprecedented organocesium architectures. Moreover, this article also highlights the first use of mild cesium carbonate as a cesium source for the construction of cesium organometallic scaffolds. Relativistic DFT calculations provide an insight into the electronic structure of the reported compounds.

Gunawan, S., & Hulme, C. (2013). Bifunctional building blocks in the Ugi-azide condensation reaction: A general strategy toward exploration of new molecular diversity. Organic and Biomolecular Chemistry, 11(36), 6036-6046.

PMID: 23912086;PMCID: PMC3795786;Abstract:

1,5-Disubstituted tetrazoles are an important drug-like scaffold known for their ability to mimic the cis-amide bond conformation. The scaffold is readily accessible via substitution of the carboxylic acid component of the Ugi multi-component reaction (MCR) with TMSN3 in what is herein denoted the Ugi-azide reaction. This full paper presents a concise, novel, general strategy to access a plethora of new heterocylic scaffolds utilizing tethered aldo/keto-acids/esters in the Ugi-azide reaction followed by a ring closing event that generates novel highly complex bis-heterocyclic lactam-tetrazoles. This journal is © The Royal Society of Chemistry.