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Research Abstracts Online
January 2009 - March 2010

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University of Minnesota Twin Cities
College of Pharmacy
Department of Medicinal Chemistry

PI: Daniel A. Harki

Development of Small Molecules Targeting Nucleotide Biosynthesis Enzymes and Transcription Factors

Currently there are two ongoing projects in the Harki laboratory. One study investigates L-nucleoside-based inhibitors of the cellular enzyme guanosine monophosphate synthetase (GMPS) as a novel strategy for developing anticancer agents. L-nucleosides are "mirror image” enantiomers of natural D-nucleosides that generally possess improved "drug-like” properties and specificities. Although L-nucleosides have been widely explored for the development of antiviral agents, their utilities as potential cancer therapeutics are significantly understudied. This researcher aims to develop L-nucleosides to inhibit enzymes in cellular nucleotide biosynthesis, such as GMPS, to regulate aberrant cell growth. A separate study develops small molecule inhibitors of the transcription factor NF-κB, a major contributor to cellular inflammatory responses. One particular molecule, helenalin, covalently modifies two cysteine residues in the DNA-binding face of NF-κB and inhibits NF-κB-DNA binding. The researcher is synthesizing helenalin analogues and evaluating their activities in cell culture in an effort to identify more potent inhibitors of NF-κB. This uses molecular modeling applications, such as Spartan, macromodel, etc., to assist in the design of new compounds to synthesize and text experimentally. Access to MSI resources greatly benefits the drug discovery efforts of this research program.

Group Members

Tianshun Hu, Research Associate
Fred A. Meece, Research Associate
Nicholas Struntz, Graduate Student
Dan Wang, Graduate Student
Brian R. White, Graduate Student