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Professor, BIO5 Institute
Professor, Pharmacology and Toxicology
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.
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.
Lynch, V. M., Hulme, C., Magnus, P., & Davis, B. E. (1995). Novel 2- and 5-azido-N-(diphenylcarbamoyl)proline methyl esters. Examples of a novel proline oxidation.. Acta crystallographica. Section C, Crystal structure communications, 51, Pt 12/-.
The crystal structures of two azido-substituted proline derivatives are reported. Racemic 2-azido-1-(diphenyl-carbamoyl)proline methyl ester, (I), C19H19N5O3, is resolved upon crystallization from methylene chloride-diethyl ether. The azido moieties are nonlinear with N--N--N angles of 173 (1) and 170.3 (2) degrees for (I) and (II) [cis-5-azido-N-(diphenylcarbamoyl)proline methyl ester, C19H19N5O3], respectively. Close intramolecular contacts between the carbonyl O atom of the amide and the central N atom of the azido group are found. The contact distances between N7 and O14 are 2.780 (14) and 2.815 (2) A for (I) and (II), respectively.
Lin, C., Lu, P., Yang, C., Hulme, C., & Shaw, A. Y. (2013). Structure-activity relationship study of growth inhibitory 2-styrylchromones against carcinoma cells. Medicinal Chemistry Research, 22(5), 2385-2394.
The structure-activity relationship study of 2-styrylchromones against carcinoma cell growth is discussed in the present report. Taking advantage of 2-styrylchromone as a molecular template, a series of structural modifications was carried out and examined on several carcinoma cell lines. Interestingly, AGS cells exhibited more sensitivity in response to methoxy-bearing compounds, of which compound 23 (3,4,5-trimethoxy group on ring B) showed the most potent activity with a GI50 value of 1.3 μM. Surprisingly, as methoxy groups in 12 and 24-27 were demethylated to generate their hydroxyl counterparts 28-32, none of them displayed appreciable activity against all carcinoma cells. We further confirmed the pivotal role of rigidity for growth inhibitory activity between the rigid 12 and its flexible counterpart 33. Taken together, in the present report, we have clearly demonstrated the structure-activity relationship study of 2-styrylchromones targeting carcinoma cell growth. © 2012 Springer Science+Business Media, LLC.
Hulme, C., Shaw, A. Y., Xu, Z., & Hulme, C. -. (2012). Ugi/Robinson-Gabriel reactions directed toward the synthesis of 2,4,5-trisubstituted oxazoles. Tetrahedron letters, 53(15).
This Letter discloses a novel concise synthesis of a series of 2,4,5-trisubstituted oxazoles via a tandem Ugi/Robinson-Gabriel sequence. Herein, 2,4-dimethoxybenzylamine 1 was used as an ammonia equivalent in combination with arylglyoxal 3 and supporting Ugi reagents, an isonitrile and carboxylic acid. As such the product of the acid treated Ugi intermediate is ideally configured to undergo a Robinson-Gabriel cyclodehydration reaction to yield the desired oxazole scaffold 5.
Hulme, C., Peng, J., Tang, S., Burns, C. J., Morize, I., & Labaudiniere, R. (1998). Improved procedure for the solution phase preparation of 1,4- benzodiazepine-2,5-dione libraries via Armstrong's convertible isonitrile and the Ugi reaction. Journal of Organic Chemistry, 63(22), 8021-8023.
Roberts, S. A., Martinez-Ariza, G., Dietrich, J., & Hulme, C. (2012). 2,4-Diphenyl-6-trifluoromethyl-2,3-dihydro-1H,5H-pyrrolo-[3,4-c]pyrrole-1, 3-dione. Acta Crystallographica Section E: Structure Reports Online, 68(2), o496-o497.
PMID: 22347098;PMCID: PMC3275242;Abstract:
The asymmetric unit of the title compound, C 19H 11F 3N 2O 2, contains two crystallographically unique mol-ecules which differ in the rotation of a phenyl ring and a -CF3 substituent. The dihedral angles involving the pyrrole ring and the attached phenyl ring are 62.82 (8) and 71.54 (7)° in the two molecules. The difference in the rotation of the CF3 groups with respect to the pyrrolo rings to which they are attached is 23.5(1)°. For one mol-ecule, there is a close contact between an H atom and the centroid of the phenyl ring of an adjacent mol-ecule (2.572 Å). A similar contact is lacking in the second mol-ecule. In the crystal, N - H⋯O inter-actions connect adjacent mol-ecules into a chain normal to (01 ). Crystallographically unique mol-ecules alternate along the hydrogen-bonded chains.