Duen-Ren Hou

Asymmetric Synthesis of 4-and 5-Substituted Pipecolic Esters by Ring-Closing Metathesis and Palladium-Catalyzed Formate Reduction

Asymmetric synthesis of 4- and 5-substituted pipecolic esters was achieved by the sequence of allylation, ring-closing metathesis, and palladium-catalyzed formate reduction.

Asymmetric Synthesis of (−)-Brevipolide H through Cyclopropanation of the α,β-Unsaturated Ketone

Brevipolides are 5,6-dihydro-γ-pyrone derivatives, first reported in 2004 as the inhibitors of the chemokine receptor CCR5 and exhibiting cytotoxicity against cancer cells. Starting from the C2 symmetric diene-diol 2, ent-brevipolide H was synthesized for the first time in 11 steps. The anti-addition of the sulfur ylide to the α,β-unsaturated enones was developed to give the key cyclopropane moiety. The synthetic (-)-brevipolide H showed an IC50 value of 7.7 μM against PC-3 cells.

Non-immunosuppressive triazole-based small molecule induces anticancer activity against human hormone-refractory prostate cancers: the role in inhibition of PI3K/AKT/mTOR and c-Myc signaling pathways

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.

Synthesis of Indenes by a BF3·OEt2-Mediated, One-Pot Reaction of Aryl Homopropargyl Alcohols, Aldehydes, and Arenes

A new and efficient protocol to prepare indenes is reported. Assisted by boron trifluoride diethyl etherate, the one-pot reaction of aryl homopropargyl alcohols and aldehydes in the presence of arenes yielded indene derivatives. The reaction was studied with various substrates, which suggests a cascade reaction including a sequence of Prins, Friedel-Crafts, ring-opening reactions, and Friedel-Crafts to form three C-C bonds leading to indenes.