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The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up.

In the continuous effort to identify new HIV-1 inhibitors endowed with innovative mechanisms, the dual inhibition of different viral functions would provide a significant advantage against drug-resistant variants. The HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) is the only viral-encoded enzymatic activity that still lacks an efficient inhibitor. We synthesized a library of 3,5-diamino-N-aryl-1H-pyrazole-4-carbothioamide and 4-amino-5-benzoyl-N-phenyl-2-(substituted-amino)-1H-pyrrole-3-carbothioamide derivatives and tested them against RNase H activity. We identified the pyrazolecarbothioamide derivative A15, able to inhibit viral replication and both RNase H and RNA-dependent DNA polymerase (RDDP) RT-associated activities in the low micromolar range. Docking simulations hypothesized its binding to two RT pockets. Site-directed mutagenesis experiments showed that, with respect to wt RT, V108A substitution strongly reduced A15 IC50 values (12.6-fold for RNase H inhibition and 4.7-fold for RDDP), while substitution A502F caused a 9.0-fold increase in its IC50 value for RNase H, not affecting the RDDP inhibition, reinforcing the hypothesis of a dual-site inhibition. Moreover, A15 retained good inhibition potency against three non-nucleoside RT inhibitor (NNRTI)-resistant enzymes, confirming a mode of action unrelated to NNRTIs and suggesting its potential as a lead compound for development of new HIV-1 RT dual inhibitors active against drug-resistant viruses., (© FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This paper describes the results obtained in the HPLC enantioseparation of N-thiocarbamoyl-3-(4'-biphenyl)-5-phenyl-4,5-dihydro-(1H) pyrazole on a cellulose tris(4-methylbenzoate) chiral stationary phase (OJ-3 CSP) using normal-phase and polar organic conditions. The enantioseparation factor (α=207) observed using the mixture n-hexane-2-propanol 70:30 as a mobile phase is among the highest values ever reported in enantioselective HPLC. The enantioseparation process was investigated by means of molecular modelling techniques. Chromatographic and theoretical investigations addressed the extreme affinity of the most CSP retained (S)-enantiomer to the intermolecular H bond network between the ligand thioamide group and the stationary phase O atoms., (Copyright © 2013 Elsevier B.V. All rights reserved.)

PLGA microspheres were prepared as a sustained release system for the intra-articular administration of celecoxib (CCB). The microspheres were prepared in the presence of different concentrations of dimethyl-β-cyclodextrin (DM-β-Cyd), by the simple oil-in-water emulsion/evaporation solvent method. The microspheres were evaluated as to surface morphology, size and technological properties (such as encapsulation efficiency, drug loading capacity and drug release). Ex vivo studies on cultures of human chondrocytes were performed in order to evaluate the influence of the polymeric carriers on the pharmacological activity of CCB. All systems ranged from about 1 to 5 μm in size and had a high encapsulation efficiency percentage ranging from about 80% to 90% (w/w), except for CCB-loaded-PLGA microspheres containing the highest amount of DM-β-Cyd, in which a dramatic drop in the encapsulation efficiency was observed (about 54%, w/w). FIB images evidenced the fact that the microspheres had a porous structure in the presence of the highest amount of DM-β-Cyd. The macrocycle modulated the release profiles of CCB from the microspheres, producing in some cases a zero-order kinetic release. Ex vivo biological studies demonstrated that DM-β-Cyd improved the drug's anti-inflammatory activity. Thus, CCB-loaded PLGA/cyclodextrin microspheres may have a potential therapeutic application in the treatment of osteo- and rheumatoid arthritis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A computer-aided design of novel asymmetric pyrazoles with improved enantioselective properties was performed by docking experiments starting from a model of Chiralcel OJ chiral in the stationary phase. Synthesis and HPLC experiments confirmed the theoretical prediction and led to a detailed investigation of the enantioselective recognition process. For the first time, looking at the time spent by each enantiomer in contact with the CSP during long molecular dynamic simulations, the experimental analytical trend has been reproduced., (© 2012 American Chemical Society)