Identification of a Dual Autophagy and REV-ERB Inhibitor with in Vivo Anticancer Efficacy.

The autophagy process appears as a promising target for anticancer interventions. Chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are the only FDA-approved autophagy flux inhibitors. Although diverse anticancer clinical trials are providing encouraging results, several limitations associated with the need of high dosage and long-term administration of these autophagy inhibitors are also emerging. We showed that the inhibition of REV-ERB, a nuclear receptor regulating circadian rhythm and metabolism, enhances CQ-mediated cancer cell death and identified a class of dual inhibitors of autophagy and REV-ERB displaying an in vitro anticancer activity against diverse tumor cells greatly higher than CQ. Herein, we describe our lead optimization strategy that led to the identification of compound 24 as a dual autophagy and REV-ERB inhibitor, showing improved potency in blocking autophagy, enhanced toxicity against cancer cells, optimal drug-like properties, and efficacy in a mouse xenograft model of melanoma as a single anticancer agent.

[OSSO]-Type Chromium(III) Complexes for the Reaction of CO2 with Epoxides.

In this work, four new mononuclear Cr(III) complexes (2-5) bearing bis-thioether-diphenolate, [OSSO]-type ligands, were synthesized and characterized. These complexes in combination with bis(triphenylphosphine)iminium chloride (PPNCl) promoted the coupling of CO2 with epoxides. Depending on the type of substrate and the conditions, the reaction results in the selective formation of either polycarbonate or cyclic carbonate. For example, the reactions in the presence of complex 2 led to the exclusive formation of poly(cyclohexene carbonate, PCHC) from cyclohexene oxide (CHO) (TOF up to 39 h-1 , at T=45-100 °C, time=24 h, pCO2 =20 bar, epoxide/2 (mol/mol)=1000, and PPNCl/2=0.5-2.0 mol %). Under the same conditions and PPNCl/2=0.5-5.0 mol %, the reactions of CO2 with styrene oxide (SO), epichlorohydrin (ECH), 1,2 epoxydodecane (EDD), and allyl glycidyl ether (AGE) have shown selective conversion to the corresponding cyclic carbonates (TOF up to 41 h-1 ).

Asymmetric trifluoromethylthiolation of azlactones under chiral phase transfer catalysis.

The first enantioselective method for the installation of the SCF3 group at the C-4 position of azlactones is described in the present communication under quinidinium phase transfer catalysis. The higher performance of substrates containing electron-rich 2-aryl groups at the azlactone was rationalized using DFT calculations.

Asymmetric Synthesis of α-Trifluoromethylthio-ß-Amino Acids under Phase Transfer Catalysis.

The first asymmetric α-trifluoromethylthiolation of 2-substituted isoxazolidin-5-ones was developed using Maruoka type N-spiro ammonium catalysts under phase-transfer conditions. The resulting products, containing a trifluoromethylthiolated quaternary chiral carbon, were obtained in moderate to good yields and up to 98:2 enantiomeric ratio. Moreover, the easy N-O bond cleavage provided access to undescribed α-trifluoromethylthio-ß2,2-amino acids, with promising applications in biochemistry and medicinal chemistry.

Asymmetric phase-transfer catalysed ß-addition of isoxazolidin-5-ones to MBH carbonates.

A novel high yielding, enantio- and diastereoselective protocol for the synthesis of α-allylated highly functionalised ß-amino acid derivatives by adding isoxazolidin-5-ones to MBH carbonates under asymmetric phase-transfer catalysis has been developed.