National Institute of Diabetes and Kidney Disease -
Medicinal Chemistry and Biology of Oral Insulin Mimics

The long-term goal of this research is to establish paradigms for the development of small molecule ligands for growth factor receptors and in so doing to develop orally active insulin mimetic drugs, based on the lead compound demethylasterriquinone B1 (DAQ B1). This project aims to accomplish these goals by synthesis of natural product libraries using combinatorial chemistry and their screening against a variety of receptor tyrosine kinases, by identification of the cellular proteins that bind to DAQ B1, and by direct examination of the interactions of DAQ B1 with the insulin receptor cytoplasmic domain.

	This project is being performed in collaboration with Prof. Nicholas J. G. Webster of the UC-San Diego Medical School.
Michael C. Pirrung, Yufa Liu, Liu Deng, Diana K. Halstead, Zhitao Li, John F. May, Michael Wedel, Darrell A. Austin, and Nicholas J. G. Webster, "Methyl Scanning: Total Syntheses of Demethylasterriquinone B1 and Derivatives for Identification of Sites of Interaction with and Isolation of Its Receptors," J. Am. Chem. Soc., 127, 4609 (2005).

UC Cancer Research Coordinating Committee -
Synthesis and Study of Phosphatidyl Inositol-3-kinase Inhibitors

We are interested in specific natural products of a class known to inhibit lipid kinases such as the phosphoinositol-3-kinases (PI3Ks). These enzymes play a key role in transmembrane signaling in cellular proliferation and in hormone response. Unique structural features of the lipid kinases make them susceptible to inhibition by 2,4-diacyl furans. Several modular synthetic routes to this pharmacophore unit have been designed that enable the prepration of large and diverse molecular libraries using cycloaddition reactions.

	Kinases and phosphatases work together to maintain the level of lipid phosphorylation appropriate for normal cell function.

NSF - 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.

	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).

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.

	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.
Jungsan Sohn, Brendan Kiburz, Zhitao Li, Liu Deng, Alexias Safi, Michael C. Pirrung, and Johannes Rudolph, “Inhibition of Cdc25 Phosphatases by Indolyldihydroxy-quinones,” J. Med. Chem., 46, 2580 (2003).

NSF - Enhanced Microarray Fabrication

This project will develop a novel class of oligonucleotide microarrays that will be more useful and applicable than microarrays currently available. Their capabilities will derive from the formation of much more stable duplexes, enabling the analysis of target nucleic acids with high GC content, high melting temperature, and/or extensive secondary structure. The methods to be developed will apply to both spotted and in situ synthesized microarrays.

	Microarrays are 2-dimensional surfaces bearing specific DNA sequences at known locations.
Michael C. Pirrung, Wolfgang Pieper, Krishna P. Kaliappan, and M. R. Dhananjeyan, "Combinatorial Discovery of Two-photon Photoremovable Protecting Groups," Proc. Natl. Acad. Sci. USA., 100, 12548 (2003).

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