Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1.

Pancreatic lipase (PL) is a well-known key target for the prevention and treatment of obesity. Human carboxylesterase 1A (hCES1A) has become an important target for the treatment of hyperlipidaemia. Thus, the discovery of potent dual-target inhibitors based on PL and hCES1A hold great potential for the development of remedies for treating related metabolic diseases. In this study, a series of natural triterpenoids were collected and the inhibitory effects of these triterpenoids on PL and hCES1A were determined using fluorescence-based biochemical assays. It was found that oleanolic acid (OA) and ursolic acid (UA) have the excellent inhibitory effects against PL and hCES1A, and highly selectivity over hCES2A. Subsequently, a number of compounds based on the OA and UA skeletons were synthesised and evaluated. Structure-activity relationship (SAR) analysis of these compounds revealed that the acetyl group at the C-3 site of UA (compound 41) was very essential for both PL and hCES1A inhibition, with IC50 of 0.75 µM and 0.014 µM, respectively. In addition, compound 39 with 2-enol and 3-ketal moiety of OA also has strong inhibitory effects against both PL and hCES1A, with IC50 of 2.13 µM and 0.055 µM, respectively. Furthermore, compound 39 and 41 exhibited good selectivity over other human serine hydrolases including hCES2A, butyrylcholinesterase (BChE) and dipeptidyl peptidase IV (DPP-IV). Inhibitory kinetics and molecular docking studies demonstrated that both compounds 39 and 41 were effective mixed inhibitors of PL, while competitive inhibitors of hCES1A. Further investigations demonstrated that both compounds 39 and 41 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. Collectively, we found two triterpenoid derivatives with strong inhibitory ability on both PL and hCES1A, which can be served as promising lead compounds for the development of more potent dual-target inhibitors targeting on PL and hCES1A.

Sonochemical surface functionalization of exfoliated LDH: Effect on textural properties, CO2 adsorption, cyclic regeneration capacities and subsequent gas uptake for simultaneous methanol synthesis.

To improve CO2 adsorption, amine modified Layered double hydroxide (LDH) were prepared via a two stage process, SDS/APTS intercalation was supported by ultrasonic irradiation and then followed by MEA extraction. The prepared samples were characterised using Scanning electron microscope-Energy dispersive X-ray spectroscopy (SEM-EDX), X-ray Photoelectron Spectroscopy (XPS), X-ray diffraction (XRD), Temperature Programmed Desorption (TPD), Brunauer-Emmett-Teller (BET), and Thermogravimetric analysis (TGA), respectively. The characterisation results were compared with those obtained using the conventional preparation method with consideration to the effect of sonochemical functionalization on textural properties, adsorption capacity, regeneration and lifetime of the LDH adsorbent. It is found that LDHs prepared by sonochemical modification had improved pore structure and CO2 adsorption capacity, depending on sonic intensity. This is attributed to the enhanced deprotonation of activated amino functional groups via the sonochemical process. Subsequently, this improved the amine loading and effective amine efficiency by 60% of the conventional. In addition, the sonochemical process improved the thermal stability of the adsorbent and also, reduced the irreversible CO2 uptake, CUirrev, from 0.18mmol/g to 0.03mmol/g. Subsequently, improving the lifetime and ease of regenerating the adsorbent respectively. This is authenticated by subjecting the prepared adsorbents to series of thermal swing adsorption (TSA) cycles until its adsorption capacity goes below 60% of the original CO2 uptake. While the conventional adsorbent underwent a 10 TSA cycles before breaking down, the sonochemically functionalized LDH went further than 30 TSA cycles.

Biomedical and forensic applications of combined catalytic hydrogenation-stable isotope ratio analysis.

Studies of biological molecules such as fatty acids and the steroid hormones have the potential to benefit enormously from stable carbon isotope ratio measurements of individual molecules. In their natural form, however, the body's molecules interact too readily with laboratory equipment designed to separate them for accurate measurements to be made. Some methods overcome this problem by adding carbon to the target molecule, but this can irreversibly overprint the carbon source 'signal'. Hydropyrolysis is a newly-applied catalytic technique that delicately strips molecules of their functional groups but retains their carbon skeletons and stereochemistries intact, allowing precise determination of the carbon source. By solving analytical problems, the new technique is increasing the ability of scientists to pinpoint molecular indicators of disease, elucidate metabolic pathways and recognise administered substances in forensic investigations.

Hydropyrolysis of steroids: a preparative step for compound-specific carbon isotope ratio analysis.

Compound-specific stable carbon isotope analysis by gas chromatography/combustion/isotope ratio mass spectrometry is an important method for the detection of steroid abuse in athletes. However, steroids in their natural form exhibit poor chromatographic resolution, while derivatization adds carbon thereby corrupting the starting stable isotopic composition. Hydropyrolysis is a new approach, which defunctionalizes steroids but leaves their carbon skeleton intact. The process improves chromatography, allowing the faithful measurement of carbon isotope ratios and enabling a more effective apportionment for the source of steroids and their metabolites.

Hydropyrolysis as a preparative method for the compound-specific carbon isotope analysis of fatty acids.

Compound-specific stable carbon isotope analysis by gas chromatography/combustion/isotope ratio mass spectrometry is an effective and risk-free means of investigating fatty acid metabolism. Straightforward analysis, however, leads to poor chromatographic resolution, while derivatization adds carbon thereby corrupting the starting stable isotopic composition. Hydropyrolysis is a new approach which defunctionalizes fatty acids to yield the corresponding n-alkanes thus retaining the carbon skeleton intact and improving chromatography, allowing the faithful measurement of carbon isotope ratios.