Stockdill, Jennifer L. The focus of the proposed research is the development of efficient methods for the construction of C-N bonds in the context of biologically active natural products and peptidic structures such as glycoproteins. There is significant demand for efficient syntheses of heterocyclic and peptidic structures because of their prevalence as pharmaceutical lead targets. The mentored K99 phase research will focus on the development of a methodology to access angularly-substituted decahydroquinolines. This method will enable rapid access to the recently isolated acetylcholinesterase inhibitor lycojapodine A. The independent R00 phase research will be centered on the use of nitrogen-centered radicals for new reaction methods. First, efforts will be directed toward a method for the formation of polycyclic structures containing a tertiary amine at a ring junction. This method will be utilized in the synthesis of the leuconicine family of alkaloids, which reverse vincristine resistance in KB cells. Additionally, a novel approach to the long-standing challenge of peptide ligation will be pursued. Together, the proposed methods will enable more efficient access to challenging architectures that are prevalent in natural products and will streamline the synthesis of homogeneous glycoproteins. Thus, the proposed research will improve access to important lead targets for the treatment of illnesses and to homogeneous versions of glycoproteins, which will enable studies of their function in cellular processes and diseases.

Public Health Relevance

Stockdill, Jennifer L. The proposed research is relevant to public health because it will enable rapid access to fused and bridged polycyclic tertiary amine products, thereby expediting the synthesis of bioactive small molecules. Furthermore, it will allow for an epimerization-free peptide ligation, substantially simplifying the synthetic approach toward homogeneous glycoproteins. These projects are supported by the NIH's mission to foster fundamental creative discoveries directed toward improving the Nation's ability to cure human diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Lees, Robert G
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Wayne State University
Schools of Arts and Sciences
United States
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Kondasinghe, Thilini D; Saraha, Hasina Y; Odeesho, Samantha B et al. (2017) Direct palladium-mediated on-resin disulfide formation from Allocam protected peptides. Org Biomol Chem 15:2914-2918
Arbour, Christine A; Saraha, Hasina Y; McMillan, Timothy F et al. (2017) Exploiting the MeDbz Linker To Generate Protected or Unprotected C-Terminally Modified Peptides. Chemistry 23:12484-12488
Stockdill, Jennifer L; Lopez, Alberto M; Ibrahim, Ahmad A (2015) Toward the ABCD Core of the Calyciphylline A-Type Daphniphyllum Alkaloids: Solvent non-Innocence in Neutral Aminyl Radical Cyclizations. Tetrahedron Lett 56:3503-3506
Ibrahim, Ahmad A; Golonka, Alexander N; Lopez, Alberto M et al. (2014) Rapid access to the heterocyclic core of the calyciphylline A and daphnicyclidin A-type Daphniphyllum alkaloids via tandem cyclization of a neutral aminyl radical. Org Lett 16:1072-5