No abstract

A new "single-flask" method was developed for the synthesis of imidazolidines and pyrrolidines with high stereoselectivity. First, a Schiff base was arylated with an aryne. Second, an intramolecular proton transfer took place from the methylene position to the anionic aryne ring. Third, the resultant ylide reacted with a second equivalent of the same Schiff base in situ or an electron-deficient alkene through a (3+2) cycloaddition. These sequential tandem 1,2-addition/(3+2) cycloaddition reactions led to the desired heterocycles in 63-88% yields.

Imidazolidinones and imidazolidine‐2,4‐diones are important classes of heterocyclic compounds that possess potent activities against several viruses such as dengue virus, enterovirus, hepatitis C virus (HCV), and human immunodeficiency virus (HIV). The first imidazolidinone derivative as an anti‐HIV agent was reported in 1996. Imidazolidinones inhibit HIV aspartic protease activity, and also act as CCR5 co‐receptor antagonists. Significant effort has been devoted to the design of various imidazolidinone analogues that are active against drug‐resistant HIV strains, with fewer side effects. Different scaffolds have been designed through both rational drug design strategies and computer‐aided drug design. Imidazolidinones have been found to be potent against HIV, and preclinical studies are currently in progress. There are some reports of imidazolidinones as having both anti‐HCV and anti‐dengue virus activity, and more research has yet to be done along these lines. These compounds inhibit NS3 serine protease of HCV, and NS2B‐NS3 protease of dengue virus. Pyridyl‐imidazolidinones possess very specific and potent activity against human enterovirus 71 (EV71) by targeting the EV71 capsid protein VP1, and inhibiting viral adsorption and/or viral RNA uncoating.

A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti-proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation. c-Myc overexpression replenished protein levels of cyclin D1 indicating that c-Myc was responsible for cell cycle regulation. PI3K/Akt/mTOR signaling pathways through p70S6K- and 4EBP1-mediated translational regulation are critical to cell proliferation and survival. SPS-7 significantly inhibited this translational pathway. Overexpression of Myr-Akt (constitutively active Akt) completely abolished SPS-7-induced inhibitory effect on mTOR/p70S6K/4EBP1 signaling and c-Myc protein expression, suggesting that PI3K/Akt serves as a key upstream regulator. SPS-7 also demonstrated substantial anti-tumor efficacy in an in vivo xenograft study using PC-3 mouse model. Notably, FTY720 but not SPS-7 induced a significant immunosuppressive effect as evidenced by depletion of marginal zone B cells, down-regulation of sphingosine-1-phosphate receptors and a decrease in peripheral blood lymphocytes. In conclusion, the data suggest that SPS-7 is not an immunosuppressant while induces anticancer effect against HRPC through inhibition of Akt/mTOR/p70S6K pathwaysthat down-regulate protein levels of both c-Myc and cyclin D1, leading to G1 arrest of cell cycle and subsequent apoptosis. The data also indicate the potential of SPS-7 since PI3K/Akt signalingis responsive for the genomic alterations in prostate cancer.

The framework of 2-pyridones is prevalent in biologically and medicinally important molecules. Here we report that chiral N-substituted 2-pyridones were prepared by enantioselective, organocatalytic aza-Michael additions of halogenated 2-hydroxypyridines (pyridin-2(1H)-ones) to α,β-unsaturated-1,4-dketones or 1,4-ketoesters. The reactions were optimized by the choice of solvents and systematic screening of Cinchona alkaloid-based bifunctional catalysts to achieve excellent yields and enantioselectivities (up to 98% yield and > 99% ee). Density functional theory calculations provided rationales for the observed enantioselectivity. Formal synthesis of a human rhinovirus protease inhibitor was achieved using the chiral Michael adduct generated by this method.