Design, Synthesis, and Structure-Activity Relationship Study of Pyrazolones as Potent Inhibitors of Pancreatic Lipase.

Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure-activity relationship analysis of these pyrazolones led us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor of PL (IC50 =0.30 µM). In addition, P32 displayed some selectivity over other known serine hydrolases. A molecular docking study for P32 demonstrated that the inhibitory activity of P32 towards PL could be attributed to the π-π interactions of 2-naphthyl unit (R1 ) and hydrophobic interactions of phenyl moiety (R3 ) with the active site of PL. Thus, P32 could serve as promising lead compound for the development of more efficacious and selective pyrazolones-type PL inhibitors for biomedical applications.

Discovery of natural alkaloids as potent and selective inhibitors against human carboxylesterase 2.

Human Carboxylesterase 2A (hCES2A), one of the most important serine hydrolases, plays crucial roles in the hydrolysis and the metabolic activation of a wide range of esters and amides. Increasing evidence has indicated that potent inhibition on intestinal hCES2A may reduce the excessive accumulation of SN-38 (the hydrolytic metabolite of irinotecan with potent cytotoxicity) in the intestinal tract and thereby alleviate the intestinal toxicity triggered by irinotecan. In this study, more than sixty natural alkaloids have been collected and their inhibitory effects against hCES2A are assayed using a fluorescence-based biochemical assay. Following preliminary screening, seventeen alkaloids are found with strong to moderate hCES2A inhibition activity. Primary structure-activity relationships (SAR) analysis of natural isoquinoline alkaloids reveal that the benzo-1,3-dioxole group and the aromatic pyridine structure are beneficial for hCES2A inhibition. Further investigations demonstrate that a steroidal alkaloid reserpine exhibits strong hCES2A inhibition activity (IC50 = 0.94 µM) and high selectivity over other human serine hydrolases including hCES1A, dipeptidyl peptidase IV (DPP-IV), butyrylcholinesterase (BChE) and thrombin. Inhibition kinetic analyses demonstrated that reserpine acts as a non-competitive inhibitor against hCES2A-mediated FD hydrolysis. Molecular docking simulations demonstrated that the potent inhibition of hCES2A by reserpine could partially be attributed to its strong σ-π and S-π interactions between reserpine and hCES2A. Collectively, our findings suggest that reserpine is a potent and highly selective inhibitor of hCES2A, which can be served as a promising lead compound for the development of more efficacious and selective alkaloids-type hCES2A inhibitors for biomedical applications.

[Occurrence Characteristics and Health Risks of PAHs on the Surface of Buildings and Devices in the Coking Plant].

The occurrence characteristics of polycyclic aromatic hydrocarbons (PAHs) on the surfaces of buildings and devices in a typical coking plant were analyzed with the samples from different functional zones and materials. The health risk of PAHs was also evaluated. The results showed that PAHs concentrations ranged from 8.00×10-2-1.98×102 µg·dm-2, and 22.0% wiping samples exceeded the World Trade Center Task Group(WTCTG)standard (1.45 µg·dm-2), the highest rate beyond the standard in the samples was 135. The functional zones with the high PAHs concentration were mainly located in the coking and refinery zone. The PAHs concentration on the surfaces of buildings in the coking zone was 12.1 µg·dm-2, which was the highest in all functional zones. Among the surface materials, the antirust paint contained the highest concentrations of PAHs and were over the standard rate, whereas the glass had the lowest adsorption ability for PAHs. The US Superfund Risk Assessment Method was used to evaluate the health risk of PAHs. The evaluation results showed that PAHs in the coking and refinery zones were a risk for carcinogenicity, the total carcinogenic risk value to the exposed population (3.78×10-6-1.32×10-5) was higher than the lower limit of the US EPA standard (10-6). The results could provide the scientific basis for environmental management and remediation of contaminated sites.

Catalyst-free visible-light-induced condensation to synthesize bis(indolyl)methanes and biological activity evaluation of them as potent human carboxylesterase 2 inhibitors.

A mild strategy for visible-light-induced synthesis of bis(indolyl)methanes was developed using aromatic aldehydes and indole as substrates. This reaction could be performed at room temperature under catalyst- and additive-free conditions to synthesize a series of bis(indolyl)methanes in good to excellent yields. In addition, all synthesized bis(indolyl)methanes together with ß-substituted indole derivatives synthesized according to our previous work, were evaluated for their inhibitory effect against human carboxylesterase (CES1 and CES2). Primary structure-activity relationship analysis of all tested compounds showed that the modifications of ß-substituted indole at the ß-site with another indolyl group led to a significant enhancement of the inhibitory effect on CES2, and the bisindolyl structure is essential for CES2 inhibition. These results demonstrated that these bis(indolyl)methanes are potent and selective CES2 inhibitors, which might be helpful for medicinal chemists to design and develop more potent and selective CES2 inhibitors for biomedical applications.