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Department of Defense Post-traumatic Stress Disorder Traumatic Brain Injury -
Small Molecule Activators of the TRK Receptors for Neuroprotection
Traumatic brain injury (TBI) is one of the major causes of mortality and morbidity among the active Iraqi-war military. It is also a major cause of morbidity and death in children and young adults. Loss of hippocampal neurons is a common sequela to a single traumatic brain insult. This loss can occur over a period of many days following the insult, yet despite improvements in surgical treatment of the primary insult, there are currently no therapies that provide neuroprotection to mitigate this secondary or delayed damage. Thus, even moderate brain injury is associated with poor prognosis and chronic cognitive impairment. We have an ongoing research project focused on developing neuroprotective drugs that target the nerve growth factor receptor TrkA that is based on the fungal natural product demethylasterriquinone B1. Neuroprotection and the development of therapeutic agents that can prevent neuronal injury is one of the identified research gaps in TBI. Therefore, this proposal aims to develop drugs targeting the neurotrophin receptors TrkB and TrkC. There is good reason to believe that neurotrophins may be protective in brain injury.
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This
project is being performed in collaboration with Prof. Nicholas
J. G. Webster of the UC-San Diego Medical School. |
| Bo Lin, Michael C. Pirrung, Liu Deng, Zhitao Li, Yufa Liu, and Nicholas J. G. Webster, “Neuroprotection by Small Molecule Activators of the NGF Receptor,” J. Pharmacol. Exp. Ther., 322, 59 (2007). |
University of California Cancer Research Coordinating Committee -
Synthesis and biology of syrbactin natural proteasome inhibitors
This project will prepare libraries of macrolactams based on the natural products syringolin A and glidobactin A (the syrbactins).The objective of this work is to discover novel, potent, and selective macrolactam inhibitors of the mammalian proteasome with anti-cancer activity, and to develop structure-reactivity relationships for the reaction of the macrolactams with the proteasome.
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This
project is being performed in collaboration with Prof. Andre S. Bachmann of the Cancer Center of Hawaii and the University of Hawaii-Manoa. |
| Michael C. Pirrung, Goutam Biswas, and Tannya R. Ibarra-Rivera, “Total Synthesis of Syringolin A and B,” Org. Lett., 12, 2402 (2010). |
CIRM - Stem Cell Survival
and Differentiation Through Chemical Genetics
The broad, long-term objective
of this research is the development of media for human embryonic
stem cells (hESCs) that are completely defined at the molecular
level and that include no biologically-derived components. This
project will address maintaining the cellular state and processes
appropriate to self-renewal, survival, or a specific differentiation
program by identifying specific small molecules that trigger appropriate
signal transduction.
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The differentiation
of multipotent cells derived from human cord blood to adipocytes
is indicated by the formation of oil droplets in the cells,
stained here with Oil Red O stain. This process is inhibited
by the small molecule kinase inhibitor BIO. |
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Acceleration of
Organic Reactions in Aqueous Media
This project investigates the
basic physicochemical traits and processes that underlie the acceleration
of reactions of organic compounds in water, with particular attention
to reactant hydrophobicity and aqueous solutes. It focuses particularly
on multi-component reactions, which are widely used in organic synthesis
for the assembly of desired targets from readily available feed
stocks, with a large increase in molecular complexity. Some multi-component
reactions have been shown to be significantly enhanced in aqueous
solution. This project will study reactions as a function of the
aforementioned parameters to develop predictive models and then
apply them to assess the models’ utility. |
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The hydrophobic
effect drives non-polar reactants together in water and accelerates
reaction. |
| Michael C. Pirrung
and Koushik Das Sarma, “Multi-component Reactions Are Accelerated
in Water,” J. Am. Chem. Soc., 126, 444 (2004). |
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