Origin of macromolecular crowding: Analysis of recognition mechanism of dual-template molecularly imprinted polymers by in silico prediction.

Multi-template imprinting is one of the challenge for molecular imprinting since the selectivity and binding affinity for each analyte decrease significantly compared with the corresponding molecularly imprinting polymers (MIPs) against single template. In this work, molecular crowding effect was tried to remedy the problem of imprinting reduction caused by the competition of two templates. Methacrylic acid (ACR) was used as functional monomer, ethylene dimethacrylate (EDMA) as crosslinker, and polystyrene (PS) as macromolecular crowding agent. With levofloxacin (S-OFX) as the first template, a number of compounds with varied chemical structure were chosen as the second template to investigate the imprinting effect of dual-template. When S-OFX and naproxen (S-NAP) was used as the dual-template, the imprinting factor (IF) of the resulting MIP for S-OFX was 20.1 and IF for S-NAP was 10.9. In contrast, for the single-template MIPs, IF for S-OFX was 22.4, and IF for S-NAP was 11.9. As a comparison, the IF of the DT-MIP prepared in absence of PS was only 2.3 for S-OFX and 1.0 for S-NAP. To analyze recognition mechanism of the molecular crowding-based imprinting system, molecular dynamics simulations to the chain structure of PS and binding modes between template and functional monomers was conducted by NAMD software. All the results displayed that molecular crowding is a promising method to improve the affinity of the dual-template imprinted polymer.

Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction.

In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 µM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.

Structure-based discovery of novel 4-(2-fluorophenoxy)quinoline derivatives as c-Met inhibitors using isocyanide-involved multicomponent reactions.

The c-Met kinase has emerged as a promising target for the development of small molecule antitumor agents because of its close relationship with the progression of many human cancers, poor clinical outcomes and even drug resistance. In this study, two novel series of 6,7-disubstitued-4-(2-fluorophenoxy)quinoline derivatives containing α-acyloxycarboxamide or α-acylaminoamide scaffolds were designed, synthesized, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (H460, HT-29, MKN-45, and MDA-MB-231). Most of the target compounds exhibited moderate to significant potency and possessed selectivity for H460 and HT-29 cancer cell lines. The preliminary structure-activity relationships indicated that α-acyloxycarboxamide or α-acylaminoamide as 5-atom linker contributed to the antitumor potency. Among these compounds, compound 10m (c-Met IC50 = 2.43 nM, a multitarget tyrosine kinase inhibitor) exhibited the most potent inhibitory activities against H460, HT-29 and MDA-MB-231 cell lines with IC50 of 0.14 ± 0.03 µM, 0.20 ± 0.02 µM and 0.42 ± 0.03 µM, which were 1.7-, 1.3- and 1.6-fold more active than foretinib, respectively. In addition, concentration-dependent assay and time-dependent assay indicated compound 10m can inhibit the proliferation of H460 cell in a time and concentration dependent manner. Moreover, docking studies revealed the common mode of interaction with the c-Met binding site, suggesting that 10m is a potential candidate for cancer therapy deserving further study.

Risk HLA class II alleles and amino acid residues in myeloperoxidase-ANCA-associated vasculitis.

A genome-wide association study (GWAS) indicated that myeloperoxidase-ANCA associated vasculitis (AAV) is associated with HLA-DQ. However, susceptibility alleles in these loci have been under-investigated. Here we genotyped 258 Chinese patients with myeloperoxidase-AAV and 597 healthy control individuals at HLA DRB1, DQA1, DQB1 and DPB1, and extracted the encoded amino acid sequences from the IMGT/HLA database. The replication cohort included 97 cases and 107 controls. T cell epitopes of myeloperoxidase were predicted and docked to the HLA molecules. We found DQA1∗0302 (odds ratio 2.34 (95% confidence interval 1.75-3.14)) and DQB1∗0303 (odds ratio 1.89 (1.45-2.48)) were risk alleles for myeloperoxidase-AAV. They are in overt linkage disequilibrium (r2 0.69) and the haplotype DQA1∗0302-DQB1∗0303 presents a significant risk (haplotype score 6.39) as well. Aspartate160 on the DQ α chain (odds ratio 2.06 (1.60-2.67)), encoded by DQA1∗0302, and isoleucine185 on the DQ ß chain (odds ratio 1.73 (1.38-2.18)), encoded by DQB1∗0303, both located in the α2ß2 domains, conferred significant risk for myeloperoxidase-AAV. Homologous modeling showed that DQα∗160D may confer susceptibility to myeloperoxidase-AAV by altering dimerization of the HLA molecules. Thus, more attention should be paid to the roles of amino acids in the α2ß2 domains in addition to the α1ß1 binding groove of HLA class II molecules.