Part I: Disruption of PTEN-5-HT2CR Coupling: A Potential Treatment for Restoration of 5-HT2CR Function / Part II: Rapid Total Synthesis of Cyclodepsipeptide MA026

PART I Serotonin 2C receptor (5-HT2CR) plays an important role in regulation of physiology, behavior, and dysfunction in 5-HT2CR neurotransmission may underlie some psychiatric disorders (e.g., depression, drug addiction). The association of the 5-HT2CR with protein phosphatase and tensin homologue (PTEN) has been demonstrated to limit the activity of that receptor to its native agonist. Disruption of this protein-protein interaction has been demonstrated to restore activity of 5-HT2CR. Work to develop physiologically-stable inhibitors of this protein-protein interaction will be discussed. The results of alanine scan indicated that four residues of 3L4F-F1, including Asn(I), Asp, Asn(II), and Arg, might be the key components for bindings or stabilizing the conformation. They may need to be preserved in the future design. Cyclic peptide 1, 2, peptidomimetic 31, and 56 with relatively good inhibitory effect of interfering with PTEN-5-HT2CR coupling were obtained. More peptide analogs, turn peptidomimetics, and looped conformation peptide mimetics were also provided for biological activity assay. The next set of biological data will be utilized to guide the synthesis of the next generation of molecules.

PART II Cyclodepsipeptides display a wide range of biological activities, including antitumor, antifungal, antiviral, antibacterial, anthelmintic, immunosuppressant, anti-inflammatory, and antimalarial activities. A novel cyclodepsipeptide, MA026, which has been shown to have antiviral activity, was discovered in 2002. The first total synthesis of MA026 was accomplished in solution-phase synthesis by Sugawara group in Japan in 2013. Two different strategies of synthesis of MA026 were carried out by the combination of solid- and solution-phases peptide syntheses. The goal was to establish a rapid, efficient, and flexible synthesis method for MA026 that can provide more materials and conduct the further biological studies. The result showed the correct m/z value in high resolution mass spectrometry, but was not identical to the reported natural product 1 in the 1H NMR spectrum. The major concern was a possible exchange between an ester bond and an amide bond in the macrocyclic ring. More investigations are needed to verify the result in the future.