Aminopyridyl/Pyrazinyl Spiro[indoline-3,4′-piperidine]-2-ones As Highly Selective and Efficacious c‑Met/ALK Inhibitors

A series of novel aminopyridyl/pyrazinyl-substituted spiro­[indoline-3,4′-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1<i>R</i>)-1-(2,6-dichloro-3-fluorophenyl)­ethoxy]-3-pyridyl]-1′-methylspiro­[indoline-3,4′-piperidine]-2-one (compound <b>5b</b> or <b>SMU-B</b>) was identified as a potent, highly selective, well-tolerated, and orally efficacious c-Met/ALK dual inhibitor, which showed pharmacodynamics effect by inhibiting c-Met phosphorylation in vivo and significant tumor growth inhibitions (>50%) in GTL-16 human gastric carcinoma xenograft models

Racemates Have Much Higher Solid-State Fluorescence Efficiency than Their Levo- and Dextrorotary Enantiomers

C6-unsubstituted tetrahydropyrimidines (THPs) are compounds with a chiral carbon and strong aggregation-induced emission. The fluorescence properties of their racemates have been studied in detail, but those of their enantiomers have not. The solid-state fluorescence properties of the racemates and enantiomers of four chiral tetrahydropyrimidines (THPs <b>1</b>–<b>4</b>) have been investigated by the steady-state and time-resolved fluorescence, single-crystal X-ray structures, and HOMOs and LUMOs of their seven racemic (three of them are polymorphs), four <i>R</i>- and three <i>S</i>-enantiomeric crystals. It was found that the <i>R</i>- and <i>S</i>-enantiomers of <b>1</b>–<b>4</b> can self-assemble as <i>RS</i>-paired, <i>RS</i>-, or <i>RR</i>/<i>SS</i>-overlapped mode in their racemates and as the same <i>RR</i>/<i>SS</i>-overlapped mode in their <i>R</i>- and <i>S</i>-enantiomers. Unexpectedly, the solid-state fluorescence quantum yields (Φ_SF) of racemic <b>1</b>–<b>4</b> could increase to 93, 48, 80, and 100%, respectively, via a suitable heteroenantiomeric self-assembly, but the Φ_SF values of their seven enantiomers are only 25–46%, owing to much larger nonradiative rate constants than those of their racemates. This means that heteroenantiomeric self-assembly can be used as a new efficient method enhancing Φ_SF values. The advantage of racemates is first reported and expected to encourage the development and application of racemates as a new kind of fluorescent materials

Molecular Simulation Studies on the Binding Selectivity of Type‑I Inhibitors in the Complexes with ROS1 versus ALK

ROS1 and ALK are promising targets of anticancer drugs for non-small-cell lung cancer. Since they have 49% amide acid sequence homology in the kinases domain and 77% identity at the ATP binding area, some ALK inhibitors also showed some significant responses for ROS1 in the clinical trial, such as the type-I binding inhibitor crizotinib and PF-06463922. As a newly therapeutic target, the selective ROS1 inhibitor is relatively rare. Moreover, the molecular basis for the selectivity of ROS1 versus ALK still remains unclear. In order to disclose the binding preference toward ROS1 over ALK and to aid the design of selective ROS1 inhibitors, the specific interactions and difference of conformational changes in the dual and selective ROS1/ALK inhibitors systems were investigated by molecular dynamics (MD) simulation and principle component analysis (PCA) in our work. Afterward, binding free energies (MM/GBSA) and binding free energies decomposition analysis indicated that the dominating effect of Van der Waals interaction drives the specific binding process of the type-I inhibitor, and residues of the P-loop and the DFG motif would play an important role in selectivity. On the basis of the modeling results, the new designed compound <b>14c</b> was verified as a selective ROS1 inhibitor versus ALK, and SMU-B was a dual ROS1/ALK inhibitor by the kinase inhibitory study. These results are expected to facilitate the discovery and rational design of novel and specific ROS1 inhibitors

Resveratrol Reactivates Latent HIV through Increasing Histone Acetylation and Activating Heat Shock Factor 1

The persistence of latent HIV reservoirs presents a significant challenge to viral eradication. Effective latency reversing agents (LRAs) based on “shock and kill” strategy are urgently needed. The natural phytoalexin resveratrol has been demonstrated to enhance HIV gene expression, although its mechanism remains unclear. In this study, we demonstrated that resveratrol was able to reactivate latent HIV without global T cell activation in vitro. Mode of action studies showed resveratrol-mediated reactivation from latency did not involve the activation of silent mating type information regulation 2 homologue 1 (SIRT1), which belonged to class-3 histone deacetylase (HDAC). However, latent HIV was reactivated by resveratrol mediated through increasing histone acetylation and activation of heat shock factor 1 (HSF1). Additionally, synergistic activation of the latent HIV reservoirs was observed under cotreatment with resveratrol and conventional LRAs. Collectively, this research reveals that resveratrol is a natural LRA and shows promise for HIV therapy

Molecular Modeling Application on Hapten Epitope Prediction: An Enantioselective Immunoassay for Ofloxacin Optical Isomers

To deepen our understanding of the physiochemical principles that govern hapten–antibody recognition, ofloxacin enantiomers were chosen as a model for epitope prediction of small molecules. In this study, two monoclonal antibodies (mAbs) mAb-WR1 and mAb-MS1 were raised against <i>R</i>-ofloxacin and <i>S</i>-ofloxacin, respectively. The enantioselective mAbs have a high sensitivity and specificity, and the enantioselectivity is not affected by heterologous coating format reactions. The epitopes of the ofloxacin isomers were predicted using the hologram quantitative structure–activity relationship (HQSAR) and comparative molecular field analysis (CoMFA) approaches. The results consistently show that the epitope of the chiral hapten should be primarily composed of the oxazine ring and the piperazinyl ring and mAbs recognize the hapten from the side of this moiety. The enantioselectivity of mAbs is most likely due to the steric hindrance caused by the stereogenic center of the epitope. Modeling of chiral hapten–protein mimics reveals that ofloxacin isomers remain upright on the surface of the carrier protein. Suggestions to improve the enantioselectivity of antibodies against ofloxacin isomers were also proposed. This study provided a simple, efficient, and general method for predicting the epitopes of small molecules via molecular modeling. The epitope predictions for small molecules may create a theoretical guide for hapten design