The purpose of this application is to develop streamlined approaches to proven polyclic guanidine containing pharmacopcore structures. Several propargylcyanamide or propargylguanidine cyclization reactions developed in our laboratory will be deployed to understand the unique biological activities of naamidine A and NA22598. By characterizing the mode of action of these natural products we will create tools to further our understanding of signaling pathways commonly associated with cancer. Understanding the molecular binding of naamidine A to ERK 1/2, will create the foundation for the development of new and unique therapeutics as the role of allostery in kinase signaling is an emerging therapeutic area. If NA22598A1 is an MMP inhibitor it would represent an important advance in pharmacophore design to inhibit this highly prized target for the treatment of numerous cancers including gastric and pancreatic carcinomas, multiple myeloma and non-small cell lung cancer. With the understanding that these small molecules will be powerful tools to study signaling processes associated with cancer, we are committed to their public availability to aid in studies outside the scope of our laboratory.
The purpose of this application is to develop new chemistry to access important and medicinally relevant natural product architectures. This chemistry permits conceptually new approaches to nitrogen rich heterocycles poised to better human health. Specifically, this chemistry will be deployed to understand the biological mode of action of two natural products capable of selectively modulating cancer-signaling pathways.
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|Gibbons, Joseph B; Salvant, Justin M; Vaden, Rachel M et al. (2015) Synthesis of Naamidine A and Selective Access to N(2)-Acyl-2-aminoimidazole Analogues. J Org Chem 80:10076-85|
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|Kwon, Ki-Hyeok; Serrano, Catherine M; Koch, Michael et al. (2014) Synthesis of bicyclic guanidines via cascade hydroamination/Michael additions of mono-N-acryloylpropargylguanidines. Org Lett 16:6048-51|
|Basham, Kaitlin J; Bhonde, Vasudev R; Kieffer, Collin et al. (2014) Bis-aryloxadiazoles as effective activators of the aryl hydrocarbon receptor. Bioorg Med Chem Lett 24:2473-6|
|Yang, Miao; Odelberg, Shannon J; Tong, Zongzhong et al. (2013) Cationic dirhodium carboxylate-catalyzed synthesis of dihydropyrimidones from propargyl ureas. Tetrahedron 69:5744-5750|
|Gligorich, Keith M; Vaden, Rachel M; Shelton, Dawne N et al. (2013) Development of a screen to identify selective small molecules active against patient-derived metastatic and chemoresistant breast cancer cells. Breast Cancer Res 15:R58|
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