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

Hulme, C., Moriarty, K., Miller, B., Mathew, R., Ramanjulu, M., Cox, P., Souness, J., Page, K. M., Uhl, J., Travis, J., Huang, F., Labaudiniere, R., & Djuric, S. W. (1998). The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I. Bioorganic and Medicinal Chemistry Letters, 8(14), 1867-1872.

PMID: 9873449;Abstract:

This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds described contain an indole moiety which replaces the 'rolipram- like' 3-methoxy-4-cyclopentoxy motif. Several of the compounds presented possess low nanomolar IC50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-α levels in LPS challenged mice (mouse endotoxemia model) are also reported.

Nichol, G. S., Gunawan, S., Zhigang, X. u., Dietrich, J., & Hulme, C. (2010). 2-Propyl 3,3-dibromo-2-hydroxypyrrolidine-1-carboxylate. Acta Crystallographica Section E: Structure Reports Online, 66(3), o597.

PMID: 21580358;PMCID: PMC2983708;Abstract:

The title compound, C8H13Br2NO 3, crystallizes as a non-merohedral twin with twin law -0.6 0 0.4/0 - 1 0 /1.6 0 0.6, and the structure has a refined twin domain ratio of 0.546 (5). The structure shows a compact conformation, with the ester unit roughly coplanar with a mean plane fitted through the non-H atoms of the pyrrolidine ring [dihedral angle = 8.23 (9)°]. In the crystal, inversion dimers linked by pairs of O - H⋯O hydrogen bonds generate an R 22(12) motif.

Hulme, C., Mathew, R., Moriarty, K., Miller, B., Ramanjulu, M., Cox, P., Souness, J., Page, K. M., Uhl, J., Travis, J., Labaudiniere, R., Huang, F., & Djuric, S. W. (1998). Orally active indole N-oxide PDE4 inhibitors. Bioorganic and Medicinal Chemistry Letters, 8(21), 3053-3058.

PMID: 9873675;Abstract:

This communication describes the synthesis and in vitro and in vivo evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. Several of the compounds presented possess low nanomolar IC50's for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-α levels in LPS challenged mice (mouse endotoxemia model). Emesis studies (dog) and efficacy in a SCW arthritis model for the most potent PDE4 inhibitors are presented.

Hulme, C., Liang, M. a., Romano, J. J., Morton, G., Tang, S., Cherrier, M., Choi, S., Salvino, J., & Labaudiniere, R. (2000). Novel applications of carbon dioxide/MeOH for the synthesis of hydantoins and cyclic ureas via the Ugi reaction. Tetrahedron Letters, 41(12), 1889-1893.

Abstract:

This communication reveals novel applications of the CO2/MeOH reagent combination coupled with the UDC (Ugi/DeBOC/Cyclize) strategy. The Ugi five component condensation (5CC) affords carbamate protected amino-amides in good yield. When one of the supporting reagents employed in the Ugi reaction possesses a tethered amino-BOC protected functional group, subsequent acid treatment and proton scavenging results in rapid cyclization to cyclic ureas. Additionally, treatment of the 5CC product with base affords hydantoins in good yield, representing a novel and short approach to this class of molecule. (C) 2000 Elsevier Science Ltd.

Magnus, P., Roe, M. B., & Hulme, C. (1995). New trialkylsilyl enol ether chemistry: Direct 1,2-bis-azidonation of triisopropylsilyl enol ethers: An azido-radical addition process promoted by TEMPO. Journal of the Chemical Society, Chemical Communications, 263-265.

Abstract:

Treatment of triisopropylsilyl enol ethers with PhIO/TMSN3/TEMPO (cat.) -45°C results in 1,2-bis-azidonation, which appears to occur through a radical addition process; the 1-azido group can be replaced by carbon nucleophiles such as allyl, methyl, cyano, acetylene and acetonyl.