Structure-Based Optimization and Biological Evaluation of Pancreatic Lipase Inhibitors as Novel Potential Antiobesity Agents

The unusual fused b-lactone vibralactone was isolated from cultures of the basidiomycete Boreostereum vibrans and has been shown to significantly inhibit pancreatic lipase.In this study,a structure-based lead optimization of vibralactone resulted in three series of 104 analogs,among which compound C1 exhibited the most potent inhibition of pancreatic lipase,with an IC50 value of 14 nM.This activity is more than 3000-fold higher than that of vibralactone.The effect of compound C1 on obesity was investigated using high-fat diet(HFD)-induced C57BL/6 J obese mice.Treatment with compound C1 at a dose of 100 mg/kg significantly decreased HFD-induced obesity,primarily through the improvement of metabolic parameters,such as triglyceride levels.

The Effectiveness of Watermelon Endocarp Extract in Inhibiting Lipase Activity Relative to the Hypolipidemic Drugs

In the effort to prove the effectiveness of watermelon endocarp extract as a hypolipidemic, the authors have done an initial experiment of lipase inhibition with the extract. The puposes of this study are to evaluate： （1） the optimum condition of lipase in the pankreoflat tablet, （2） the effect of watermelon endocarp extract in inhibition the lipase activity, and （3） the effectiveness of watermelon endocarp extract as lipase inhibitor relative to the hypolipidemic drugs （orlistat）. Watermelon endocarp was extracted by blender, squeezed and filtered. As a source of lipase has been used pankreoflat （Kimia Farina） tablet, inhibition test was performed by mixing 35 mL with substrate （olive oil） that has been coupled with one tablet （0.25 g） ofpankreoflat and extract of 50 g watermelon endocarp and then incubated at 37℃, pH 7.5 for 25 minutes. Lipase activity is indicated by the amount ofNaOH titrant which was used to neutralize the free fatty acid from hydrolysis of olive oil. The results showed that 50 g of watermelon endocarp can produce 26 mL extract and decrease the lipase activity by 70.34%, or equivalent to 85% of the effectiveness of one tablet orlistat （120 mg）, one of the hypolipidemic drugs.

Three new polyoxygenated bergamotanes from the endophytic fungus Penicillium purpurogenum IMM 003 and their inhibitory activity against pancreatic lipase

Purpurolides D–F(1–3),three new polyoxygenated bergamotanes bearing a 6/4/5/5 tetracyclic ring system,were isolated from the endophytic fungus Penicillium purpurogenum IMM 003.Their structures were unambiguously elucidated based on extensive spectroscopic data analyses,13 C NMR chemical shifts calculations coupled with the DP4+probability method,and the calculated and experimental electronic circular dichroism(ECD)spectra.Compounds 1–3 showed significant inhibitory activity against pancreatic lipase(PL).The result highlights that the presence of 3-hydroxylated decanoic acid moiety at C-14 is important for increasing the inhibition potency against PL.

Synthesis and evaluation of benzylisoquinoline derivatives for their inhibition on pancreatic lipase and preadipocyte proliferation

The present study was designed to synthesize and evaluate a series of benzylisoquinoline derivatives. These compounds were synthesized by Bischler-Napieralski cyclization to yield 1-benzyl-3,4-dihydroisoquinolines, and the products were obtained by reductions. All these compounds were identified by MS, 1H NMR and 13 C NMR. The inhibitory activities on pancreatic lipase and preadipocyte proliferation for the synthesized compounds and alkaloids from Nulembo nucifera were assessed in vitro. Most of the compounds showed inhibitory activities on both pancreatic lipase and preadipocyte proliferation. Particularly, compounds 7p-7u and 9d-9f exhibited significant inhibitory activity on pancreatic lipase while compounds 7c, 7d, 7f, 7g, 7i, and 7j potently inhibited the proliferation of 3T3-L1 preadipocytes. Our results provided a basis for future evaluation and development of these compounds as leads for therapeutics for human diseases.