Hulme, C., Shaw, A. Y., McLaren, J. A., Nichol, G. S., & Hulme, C. -. (2012). Hydrazine-mediated cyclization of Ugi products to synthesize novel 3-hydroxypyrazoles. Tetrahedron letters, 53(21).
This report discloses a novel concise synthesis of a series of 3-hydroxypyrazoles 5 via a tandem Ugi/debenzylation /hydrazine-mediated cyclization sequence. Herein, n-butyl isocyanide 4b was utilized as an alternative to classical convertible isocyanides enabling high yielding hydrazine-mediated cyclization. Taken together, a novel class of 3-hydroxypyrazoles 5a-5i was synthesized with potential to be of interest in future library enrichment strategies.
Hulme, C., 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 Alzheimer's?. ACS chemical neuroscience, 3(11).
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 Alzheimer's 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 Alzheimer's disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimer's 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.
Hulme, C., Martinez-Ariza, G., Lee, Y., & Nunez-Rios, J. (2015). Acetyl cyanide as a cyanide source in a tandem catalyst-free [4+1] cycloaddition-Strecker cascade.. Tetrahderon Letters, 56, 1038-1040.
Hulme, C., Xu, Z., De Moliner, F., Cappelli, A. P., & Hulme, C. -. (2013). Aldol reactions in multicomponent reaction based domino pathways: a multipurpose enabling tool in heterocyclic chemistry. Organic letters, 15(11).
The aldol reaction has been evaluated in combination with the Ugi multicomponent reaction to assemble richly decorated mono- and polycyclic systems via expeditious cascade pathways. A small collection of pyrrolinones was generated thereof, and the scarcely accessible pyridoquinoxalinedione scaffold was also prepared by designing an additional nucleophilic substitution step in this domino sequence requiring minimal operational effort.
Hulme, C., Bienaymé, H., Nixey, T., Chenera, B., Jones, W., Tempest, P., & Smith, A. L. (2003). Library Generation via Postcondensation Modifications of Isocyanide-Based Multicomponent Reactions. Methods in Enzymology, 369, 469-496.
