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  • Arylquin 1 Eleutherococcus senticosus Rupt Maxim Maxim is a

    2020-07-10

    Eleutherococcus senticosus (Rupt. & Maxim.) Maxim is a shrub belonging to the Araliaceae, which is commonly distributed in China, Korea, Japan and Russia. It has been traditionally used as folk medicine for the treatment of rheumatism, diabetes, and hepatitis (Nan et al., 2004). Recent phytochemical Arylquin 1 and biological investigations of Eleutherococcus senticosus found its roots and stem Arylquin 1 include diterpenoids, triterpenoids, lignans, polyacetylenes, phenylpropanoids, diphenyl ethers and flavonoids (Ryu et al., 2004, Li et al., 2015). During the screening of DGAT inhibitors from natural sources, we found a MeOH extract of the stems of A. senticosus exhibited DGAT1 inhibitory activity (>70% inhibition at 30μg/ml) which led us to investigate this plant. Herein, we reported the isolation and structure elucidation of two new compounds along with five known compounds, and the evaluation of their DGAT1 and DGAT2 inhibitory activity (Fig. 1).
    Experimental
    Acknowledgments
    Obesity is a serious health risk that is characterized by an excess accumulation of triglycerides (TG) and can lead to a number of additional conditions including type 2 diabetes, atherosclerosis, hypertension, and cardiovascular disease. Dietary TGs are broken down in the gut to monoacylglycerol and then absorbed in the small intestines. TGs are then reassembled with the sequential addition of two acyl chains. The final step of TG synthesis is catalyzed by the enzyme acyl CoA: diacylglycerol acyltransferase (DGAT) of which there are two forms. Although both DGAT-1 and DGAT-2 are transmembrane proteins found in white adipose tissue, small intestine, liver, and mammary gland, they are from different gene families with distinctive functions. DGAT-1 knockout mice are viable, exhibit resistance to weight gain when fed a high-fat diet, have increased insulin sensitivity, and have increased leptin sensitivity. In contrast, DGAT-2 has an essential role since these knockout mice are not viable due to lipopenia and skin homeostasis abnormalities. DGAT-1 is a member of the acyl CoA: cholesterol acyltransferase (ACAT) gene family and is more homologous with ACAT-1 and ACAT-2 than with DGAT-2 which is more closely related to the monoacylglycerol acyl transferase (MGAT) enzymes. With the resistance to weight gain and positive physiological effects seen in DGAT-1 null mice, an inhibitor of DGAT-1 may be a useful therapy for obesity. The discovery of a selective DGAT-1 inhibitor has been the subject of a number of recent reviews and publications., , , , , , , , First generation DGAT-1 inhibitors from Japan Tobacco, Pfizer, Bayer, and Abbott are shown in and have a terminal carboxylic acid moiety which mimics the fatty acid substrate of DGAT-1., , , Beginning with the non-carboxylic acid, oxazole DGAT-1 inhibitors by Hoffman-LaRoche/Via Pharmaceuticals, our exploratory chemistry group began work on developing novel DGAT-1 inhibitors. Initial investigations led to the identification of the lead compound with reasonable DGAT-1 inhibitory activity. SAR optimization of compound began with left hand side analogs which were synthesized according to the route depicted in . Addition of -BOC-piperazine to 2-chloro-5-nitropyridine gave pyridyl-piperazine . Removal of the BOC protecting group and reaction with 2-fluorophenyl isocyanate provided nitro intermediate . Reduction of the nitro group by hydrogenation and HATU promoted amide formation produced the target compound . Representative examples of left hand side modifications are summarized in . From a large screen of diverse substituents, we found that the 2-piperidinyl-4-trifluoromethyl-oxazole ring could be replaced by a bicyclic indole ring in compound with increased inhibition of the human DGAT-1 enzyme in our in vitro screening assay. The bicyclic benzofuran ring in compound and benzothiophene ring in compound exhibited further improvement of DGAT-1 activity. The 3-trifluoromethyl substituent appeared to be a positive factor since the hydrogen analog displayed lower activity relative to the methyl , fluoromethyl , and difluoromethyl analogs. Substitution on the phenyl ring of the benzofuran was tolerated in analogs –.