5 research outputs found
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 spiroÂ[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)Âethoxy]-3-pyridyl]-1′-methylspiroÂ[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<sub>SF</sub>) 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<sub>SF</sub> 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<sub>SF</sub> 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