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Teva Pharmaceuticals Marc A. Goshko Memorial Grant Program Awardees 2012 - 2015

Dr. Phil S. Baran
Scripps Research Institute

“Scalable Routes to Complex Terpenes.”

The Baran laboratory has been interested in a “two-phase” strategy toward the synthesis of complex terpene natural products such as eudesmanes, taxanes and ingenanes. We wish to further explore and expand the potential scope of this strategy by: 1) developing an efficient and scalable “cyclase phase” to the ent-kaurane and ent-atisane families of natural products; 2) testing the efficiency and selectivity of the ensuing “oxidase phase” in order to target various oxidation levels in the bioactive ent-kaurane family of natural products; and 3) using a semi-synthetic approach as an expedient cyclase phase equivalent and executing a “redox-relay strategy” in the oxidase phase toward a scalable synthesis of ouabain, a cardiotonic steroid. These natural product families offer an ideal opportunity to put into practice the two-phase paradigm and to explore the uncharted realm of chemoselective oxidations during the oxidase phase.

Other than allowing to procure chemicals and pay student stipends, the TEVA grant has allowed for the creation of an educational platform through organic synthesis and has generated a desire to continue pushing the boundaries of chemical feasibility.

Dr. Phil S. Baran

Dr. John Lavigne
University of South Carolina

“Synthetic Lectins: New Tools for Detection and Management”

Our goal is to develop synthetic lectin arrays for diagnosing cancer by detecting abnormal glycosylation events known to occur during oncogenesis and continue as the cancer progresses.  Instead of relying on the recognition of a single and often variable biomarker, our approach relies on the recognition of general glycosylation patterns and does not require prior knowledge of targeted glycans.  Consequently, we are interested in producing a composite snapshot of many unique biomarkers, i.e. a fingerprint, thus providing a complete qualitative cellular profile.  As a result of the support provided by Teva Pharmaceuticals we have been able to: 1) streamline the development process and assay response by moving from static microscopy-based methods to dynamic flow-based analyses; 2) advance previous work that could detect the desired glycosylation changes in membrane-bound glycoproteins to also demonstrating our ability to detect these changes in secreted glycoproteins; 3) enhance our discovery process relying on more clinically relevant screening approaches as compared to commercially available, purified glycoproteins; and 4) identify many of the fundamental bases for analyte binding using synthetic lectins.  What this all boils down to is that thanks to Teva Pharmaceuticals, we have been able to advance our work from a relatively slow and monotonous cell-based assay to a greatly simplified, rapid serum-based assessment, thus achieving a diagnostic that is more amenable for use in the real-world.  We have also been able to better target our synthetic lectins towards more clinically relevant scenarios while also enhancing the quality of our chemical interactions thereby providing improved assay sensitivity.

 Dr. John Lavigne

Dr. Ming Xian
Washington State University

“Explore New Molecular Entities for Hydrogren Sulfide Research"

“Hydrogen sulfide (H2S) is an important redox signaling molecule. H2S’s biological action is centered on its reactivity toward heme-proteins and its ability to activate KATP channels. Although the exact mechanisms of action are still under investigation, the production of endogenous H2S and the exogenous administration of H2S have been demonstrated to exert protective effects in many pathologies.  It is important, therefore, to develop suitable H2S releasing agents. These compounds not only can be useful research tools, but also have potential therapeutic benefits. In this project we are studying new chemistry of H2S and sulfide containing compounds. Our goal is to develop a series of long-lasting and controllable H2S releasing agents. We are especially focusing on H2S donor conjugates such as H2S-nitric oxide donor hybrids and H2S-nonsteroidal anti-inflammatory drug hybrids.  Cytoprotective activity and anti-inflammatory activity of these donors/conjugates will also be investigated.

"We thank the ACS-TEVA award which supports our exploratory research in this exciting field of hydrogen sulfide chemical biology."

Dr. Ming Xian