The goal of this research is to develop improved chemistry to transform simple peptides into products lacking or with reduced numbers of amide functional groups, in some cases temporarily. The chemistry we aim to develop has its origins in biosynthesis, wherein enzymes activate amide functional groups towards nucleophilic attack by various side chains leading to the formal intramolecular cyclodehydration of the participating amide resulting in oxazoline and thiazoline ring formation. One third of this proposal will focus on developing synthetic methodology to convert peptides into heterocycles irreversibly with retention of Calpha and Cbeta stereochemistry. The availability of a wide variety of alpha- and beta-amino acids allows the synthesis of peptides tailored to produce the desired imidates, thiomidates and related structures. A variety of side chain protected and unprotected peptides will be synthesized to scrutinize the efficiency, as well as the regio- and stereoselectivity of the formation of a spectrum of heterocycles. The second portion of this proposal will focus on developing methodology to reversibly mask amide functional groups in peptides to make them bioavailable. Amide bonds will be converted to imidate esters, or the like, with favorable membrane translocation properties to facilitate cellular and/or oral bioavailability, where subsequent hydrolysis regenerates the peptide. The membrane translocation properties of neutral imidate, thioimidate or similar backbones should be dramatically improved as a result of the reduction in the number of hydrogen bond donors and acceptors, which correlates with peptide membrane translocation ability. The cationic masked amides aim to take advantage of a newly discovered active transport system to mediate membrane translocation. Making peptides and proteins generally bioavailable is the long term goal of this specific aim. The remaining specific aim will focus on evaluating the biological activity of the heterocyclic and acyclic imidate and thioimidate products produced in this project. We will concentrate on antibacterial activity, particularly towards resistant strains, RNA binding, and antitumor activity. In the first and the third cases, these compounds will be submitted to screens at Novartis and the National Cancer Institute, respectively. In the second case, fused heterocyclic libraries will be prepared and their interactions with RNA targets evaluated by our Scripps collaborator Jamie Williamson.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Lograsso, Philip
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Scripps Research Institute
La Jolla
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Efron, Philip A; Matsumoto, Tadashi; McAuliffe, Priscilla F et al. (2009) Major hepatectomy induces phenotypic changes in circulating dendritic cells and monocytes. J Clin Immunol 29:568-81
Tsujimoto, Hironori; Ono, Satoshi; Majima, Takashi et al. (2006) Differential toll-like receptor expression after ex vivo lipopolysaccharide exposure in patients with sepsis and following surgical stress. Clin Immunol 119:180-7
Efron, Philip A; Tinsley, Kevin; Minnich, Douglas J et al. (2004) Increased lymphoid tissue apoptosis in baboons with bacteremic shock. Shock 21:566-71
Efron, Philip A; Moldawer, Lyle L (2004) Cytokines and wound healing: the role of cytokine and anticytokine therapy in the repair response. J Burn Care Rehabil 25:149-60
You, Shu-Li; Kelly, Jeffery W (2004) Highly efficient biomimetic total synthesis and structural verification of bistratamides E and J from Lissoclinum bistratum. Chemistry 10:71-5
You, Shu-Li; Deechongkit, Songpon; Kelly, Jeffery W (2004) Solid-phase synthesis and stereochemical assignments of tenuecyclamides A-D employing heterocyclic amino acids derived from commercially available Fmoc alpha-amino acids. Org Lett 6:2627-30
You, Shu-Li; Kelly, Jeffery W (2004) Highly efficient enantiospecific synthesis of imidazoline-containing amino acids using bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate. Org Lett 6:1681-3
You, Shu-Li; Razavi, Hossein; Kelly, Jeffery W (2003) A biomimetic synthesis of thiazolines using hexaphenyloxodiphosphonium trifluoromethanesulfonate. Angew Chem Int Ed Engl 42:83-5
Efron, Philip; Moldawer, Lyle L (2003) Sepsis and the dendritic cell. Shock 20:386-401
You, Shu-Li; Kelly, Jeffery W (2003) Total synthesis of dendroamide a: oxazole and thiazole construction using an oxodiphosphonium salt. J Org Chem 68:9506-9

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