Hulme, C., Medda, F., Sells, E., Chang, H., Dietrich, J., Chappeta, S., Smith, B., Gokhale, V., Meuillet, E. J., & Hulme, C. -. (2013). Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells. Bioorganic & medicinal chemistry letters, 23(2).
This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE(2) reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R(1)=H, R(2)=p-CH(3)O) exhibited the most potent activity in cells (EC(50)=0.02 μM) and minimal inhibition of COX-2 activity (3% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.
Hulme, C., Chappeta, S., & Dietrich, J. (2009). A simple, cheap alternative to 'designer convertible isonitriles' expedited with microwaves. Tetrahedron Letters, 50(28), 4054-4057.
Abstract:
Interest in designer convertible isonitriles has increased in recent years with the growing recognition that isonitrile-based multi-component reactions (IMCRs) are highly effective in rapidly accessing, new and pharmacologically relevant diversity space. This Letter reports on the novel use of n-butylisonitrile as a cheaper and more atom-economical alternative to currently reported 'designer convertible isonitriles', facilitated by the advent of microwave-assisted organic synthesis (MAOS).
Xu, Z., Martinez-Ariza, G., Cappelli, A. P., Roberts, S. A., & Hulme, C. (2015). (Z)-Stereoselective Synthesis of Mono- and Bis-heterocyclic Benzimidazol-2-ones via Cascade Processes Coupled with the Ugi Multicomponent Reaction. The Journal of organic chemistry, 80(18), 9007-15.
Several novel cascade reactions are herein reported that enable access to a variety of unique mono- and bis-heterocyclic scaffolds. The sequence of cascade events are mediated through acid treatment of an Ugi adduct that affords 1,5-benzodiazepines which subsequently undergo an elegant rearrangement to deliver (E)-benzimidazolones, which through acid-promoted tautomerization convert to their corresponding (Z)-isomers. Moreover, a variety of heterocycles tethered to (Z)-benzimidazole-2-ones are also accessible through similar domino-like processes, demonstrating a general strategy to access significantly new scaffold diversity, each containing four points of potential diversification. Final structures of five scaffolds have been definitively proven by X-ray crystallography.
Magnus, P., Hulme, C., & Weber, W. (1994). α-Azidonation of amides, carbamates, and ureas with the iodosylbenzene/trimethylsilyl azide reagent combination: N-acyliminium ion precursors. Journal of the American Chemical Society, 116(10), 4501-4502.
Hulme, C., Chappeta, S., Griffith, C., Lee, Y., & Dietrich, J. (2009). An efficient solution phase synthesis of triazadibenzoazulenones: 'designer isonitrile free' methodology enabled by microwaves. Tetrahedron Letters, 50(17), 1939-1942.
Abstract:
A novel two-step solution phase protocol for the synthesis of arrays of triazadibenzoazulenones is reported. The methodology employs the Ugi reaction to assemble desired diversity and acid treatment enables two tandem ring closing transformations. The order of ring closure is shown to be key for optimal conversion to the desired tetra-cyclic product and initially proceeds through a benzimidazole intermediate, followed by second ring closure to give the desired fused benzodiazepine. The two-step protocol is further facilitated by microwave irradiation. Prudent selection of the isonitrile reagent enables the correct order of ring forming events. As such the methodology represents the first example of a post-condensation Ugi modification that employs two internal amino nucleophiles. © 2009 Elsevier Ltd. All rights reserved.
