Design, synthesis, and biological evaluation of N-(pyridin-3-yl)pyrimidin-4-amine analogues as novel cyclin-dependent kinase 2 inhibitors for cancer therapy.

The discovery and development of CDK2 inhibitors has currently been validated as a hot topic in cancer therapy. Herein, a series of novel N-(pyridin-3-yl)pyrimidin-4-amine derivatives were designed and synthesized as potent CDK2 inhibitors. Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC50 values of 0.83, 2.12, 3.12, and 8.61 µM, respectively, which were comparable to that of Palbociclib and AZD5438. Interestingly, these compounds were less toxic on normal embryonic kidney cells HEK293 with high selectivity index. Further mechanistic studies indicated 7l caused cell cycle arrest and apoptosis on HeLa cells in a concentration-dependent manner. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC50 of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.

Synthesis and biological evaluation of novel 5-substituted/unsubstituted triazolothiadiazines as tubulin depolymerizing and vascular disrupting agents with promising antitumor activity.

A novel series of 5-substituted/unsubstituted [1,2,4]triazolo[3,4-b][1,3,4] thiadiazine compounds has been achieved successfully through chemoselective reduction of the C = N bond, based on our prior work. Initial biological evaluation illustrated that the most active derivative 7j exhibited significant cell growth inhibitory activity toward MCF-7, A549, HCT116, and A2780 with the IC50 values of 0.75, 0.94, 2.90, and 4.15 µM, respectively. Most importantly, all the representative analogs did not demonstrate obvious cytotoxic activity against the non-tumoural cell line HEK-293 (IC50 > 100 µM). The mechanism study revealed that 7j caused the G2 /M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, 7j exerted significant antivascular activity in the wound-healing and tube formation assays. These observations indicate that 5-unsubstituted 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold might be considered as a potential lead for antitubulin inhibitors to develop highly efficient anticancer agents with potent selectivity over normal human cells.

Ligand-based discovery of coronavirus main protease inhibitors using MACAW molecular embeddings.

Ligand-based drug design methods are thought to require large experimental datasets to become useful for virtual screening. In this work, we propose a computational strategy to design novel inhibitors of coronavirus main protease, Mpro. The pipeline integrates publicly available screening and binding affinity data in a two-stage machine-learning model using the recent MACAW embeddings. Once trained, the model can be deployed to rapidly screen large libraries of molecules in silico. Several hundred thousand compounds were virtually screened and 10 of them were selected for experimental testing. From these 10 compounds, 8 showed a clear inhibitory effect on recombinant Mpro, with half-maximal inhibitory concentration values (IC50) in the range 0.18-18.82 µM. Cellular assays were also conducted to evaluate cytotoxic, haemolytic, and antiviral properties. A promising lead compound against coronavirus Mpro was identified with dose-dependent inhibition of virus infectivity and minimal toxicity on human MRC-5 cells.

Predictive and explanatory themes of NOAEL through a systematic comparison of different machine learning methods and descriptors.

No observed adverse effect level (NOAEL) is an identified dose level which used as a point of departure to infer a safe exposure limit of chemicals, especially in food additives and cosmetics. Recently, in silico approaches have been employed as effective alternatives to determine the toxicity endpoints of chemicals instead of animal experiments. Several acceptable models have been reported, yet assessing the risk of repeated-dose toxicity remains inadequate. This study established robust machine learning predictive models for NOAEL at different exposure durations by constructing high-quality datasets and comparing different kinds of molecular representations and algorithms. The features of molecular structures affecting NOAEL were explored using advanced cheminformatics methods, and predictive models also communicated the NOAEL between different species and exposure durations. In addition, a NOAEL prediction tool for chemical risk assessment is provided (available at: https://github.com/ifyoungnet/NOAEL). We hope this study will help researchers easily screen and evaluate the subacute and sub-chronic toxicity of disparate compounds in the development of food additives in the future.

A novel multi-layer prediction approach for sweetness evaluation based on systematic machine learning modeling.

Nowadays, computational approaches have drawn more and more attention when exploring the relationship between sweetness and chemical structure instead of traditional experimental tests. In this work, we proposed a novel multi-layer sweetness evaluation system based on machine learning methods. It can be used to evaluate sweet properties of compounds with different chemical spaces and categories, including natural, artificial, carbohydrate, non-carbohydrate, nutritive and non-nutritive ones, suitable for different application scenarios. Furthermore, it provided quantitative predictions of sweetness. In addition, sweetness-related chemical basis and structure transforming rules were obtained by using molecular cloud and matched molecular pair analysis (MMPA) methods. This work systematically improved the data quality, explored the best machine learning algorithm and molecular characterizing strategy, and finally obtained robust models to establish a multi-layer prediction system (available at: https://github.com/ifyoungnet/ChemSweet). We hope that this study could facilitate food scientists with efficient screening and precise development of high-quality sweeteners.

Visual Detection of Adenosine Triphosphate by Taylor Rising: A Simple Point-of-Care Testing Method Based on Rolling Circle Amplification.

Rapid and sensitive point-of-care testing (POCT) is an extremely critical mission in practical applications, especially for rigorous military medicine, home health care, and in the third world. Here, we report a visual POCT method for adenosine triphosphate (ATP) detection based on Taylor rising in the corner of quadratic geometries between two rod surfaces. We discuss the principle of Taylor rising, demonstrating that it is significantly influenced by contact angle, surface tension, and density of the sample, which are controlled by ATP-dependent rolling circle amplification (RCA). In the presence of ATP, RCA reaction effectively suppresses Taylor-rising behavior, due to the increased contact angle, density, and decreased surface tension. Without addition of ATP, untriggered RCA reaction is favorable for Taylor rising, resulting in a significant height. With this proposed method, visual sensitive detection of ATP without the aid of other instruments is realized with only a 5 µL droplet, which has good selectivity and a low detection limit (17 nM). Importantly, this visual method provides a promising POCT tool for user-friendly molecular diagnostics.

Oxycodone vs Sufentanil in Patient-Controlled Intravenous Analgesia After Gynecological Tumor Operation: A Randomized Double-Blind Clinical Trial.

BACKGROUND: This study aims to compare analgesic effect and side effects of oxycodone and sufentanil in transition analgesia and patient-controlled intravenous analgesia (PCIA) after gynecological tumor operation under general anesthesia. PATIENTS AND METHODS: A prospective, randomized, double-blind research was conducted. Patients undergoing elective gynecological tumor surgery were randomized into four groups: Group S (sufentanil transition analgesia and sufentanil PCIA), Group OS (oxycodone transition analgesia and sufentanil PCIA), Group SO (sufentanil transition analgesia and oxycodone PCIA) and Group O (oxycodone transition analgesia and oxycodone PCIA). The primary outcomes were Numerical Rating Scale (NRS) at rest and coughing, accumulated opioid consumption in PCIA and patients' satisfaction. RESULTS: Patients in Group OS and Group O showed shorter time of consciousness recovery and extubation after surgery. Accumulated opioid consumption in PCIA (equal to morphine) in Group SO and Group O was significantly less than that in Group S and Group OS. Patients in Group O showed lower NRS at rest and coughing, but higher patients' satisfaction 3, 24 and 48 hours after surgery. Patients in Group SO and Group O showed a shorter time of intestinal recovery, first feeding and first-time movement. CONCLUSION: Both oxycodone and sufentanil provided adequate pain relief in transitional analgesia and PCIA treatment after surgery. Oxycodone without background infusion showed less analgesic drug consumption and faster recovery than sufentanil with background infusion in PCIA after gynecological tumor operation under general anesthesia.

Prognostic significance of DAPK promoter methylation in lymphoma: A meta-analysis.

We aimed to characterize the clinical significance of epigenetic loss of death-associated protein kinase (DAPK) gene function through promoter methylation in the development and prognosis of lymphoma. PubMed, Web of Science and ProQuest databases were searched for relevant studies. Twelve studies involving 709 patients with lymphoma were identified. The prognostic value of DAPK methylation was expressed as risk ratio (RR) and its corresponding 95% confidence interval (CI), while the associations between DAPK methylation and the clinical characteristics of patients with lymphoma were expressed as odd ratios (ORs) and their corresponding 95% CIs. Meta-analysis showed that the 5-year survival rate was significantly lower in lymphoma patients with hypermethylated DAPK (RR = 0.85, 95% CI (0.73, 0.98), P = 0.025). Sensitivity analysis demonstrated consistent result. However, no associations were found between DAPK methylation and clinicopathological features of lymphoma, in relation to gender (OR = 1.07, 95% CI (0.72, 1.59), P = 0.751), age (OR = 1.01, 95% CI (0.66, 1.55), P = 0.974), international prognostic index (OR = 1.20, 95% CI (0.63, 2.27), P = 0.575), B symptoms (OR = 0.76, 95% CI (0.38, 1.51), P = 0.452), serum lactate dehydrogenase (OR = 1.13, 95% CI (0.62, 2.05), P = 0.683), and BCL-2 expression (OR = 1.55, 95% CI (0.91, 2.66), P = 0.106). Lymphoma patients with hypermethylated DAPK are at risk for poorer 5-year survival rate. DAPK methylation may serve as a negative prognostic biomarker among lymphoma patients, although it may not be associated with the progression of lymphoma.

ChemSAR: an online pipelining platform for molecular SAR modeling.

BACKGROUND: In recent years, predictive models based on machine learning techniques have proven to be feasible and effective in drug discovery. However, to develop such a model, researchers usually have to combine multiple tools and undergo several different steps (e.g., RDKit or ChemoPy package for molecular descriptor calculation, ChemAxon Standardizer for structure preprocessing, scikit-learn package for model building, and ggplot2 package for statistical analysis and visualization, etc.). In addition, it may require strong programming skills to accomplish these jobs, which poses severe challenges for users without advanced training in computer programming. Therefore, an online pipelining platform that integrates a number of selected tools is a valuable and efficient solution that can meet the needs of related researchers. RESULTS: This work presents a web-based pipelining platform, called ChemSAR, for generating SAR classification models of small molecules. The capabilities of ChemSAR include the validation and standardization of chemical structure representation, the computation of 783 1D/2D molecular descriptors and ten types of widely-used fingerprints for small molecules, the filtering methods for feature selection, the generation of predictive models via a step-by-step job submission process, model interpretation in terms of feature importance and tree visualization, as well as a helpful report generation system. The results can be visualized as high-quality plots and downloaded as local files. CONCLUSION: ChemSAR provides an integrated web-based platform for generating SAR classification models that will benefit cheminformatics and other biomedical users. It is freely available at: http://chemsar.scbdd.com . Graphical abstract .

BioTriangle: a web-accessible platform for generating various molecular representations for chemicals, proteins, DNAs/RNAs and their interactions.

BACKGROUND: More and more evidences from network biology indicate that most cellular components exert their functions through interactions with other cellular components, such as proteins, DNAs, RNAs and small molecules. The rapidly increasing amount of publicly available data in biology and chemistry enables researchers to revisit interaction problems by systematic integration and analysis of heterogeneous data. Currently, some tools have been developed to represent these components. However, they have some limitations and only focus on the analysis of either small molecules or proteins or DNAs/RNAs. To the best of our knowledge, there is still a lack of freely-available, easy-to-use and integrated platforms for generating molecular descriptors of DNAs/RNAs, proteins, small molecules and their interactions. RESULTS: Herein, we developed a comprehensive molecular representation platform, called BioTriangle, to emphasize the integration of cheminformatics and bioinformatics into a molecular informatics platform for computational biology study. It contains a feature-rich toolkit used for the characterization of various biological molecules and complex interaction samples including chemicals, proteins, DNAs/RNAs and even their interactions. By using BioTriangle, users are able to start a full pipelining from getting molecular data, molecular representation to constructing machine learning models conveniently. CONCLUSION: BioTriangle provides a user-friendly interface to calculate various features of biological molecules and complex interaction samples conveniently. The computing tasks can be submitted and performed simply in a browser without any sophisticated installation and configuration process. BioTriangle is freely available at http://biotriangle.scbdd.com.Graphical abstractAn overview of BioTriangle. A platform for generating various molecular representations for chemicals, proteins, DNAs/RNAs and their interactions.

In vitro and in vivo magnetic resonance imaging with chlorotoxin-conjugated superparamagnetic nanoprobes for targeting hepatocarcinoma.

The present study aimed to assess the in vitro and in vivo magnetic resonance imaging (MRI) features of chlorotoxin (CTX)-conjugated superparamagnetic iron oxide (SPIO) nanoprobes. CTX-conjugated nanoprobes were composed of SPIO coated with polyethylene glycol (PEG) and conjugated with CTX. The nanoprobes were termed SPIO-PEG-CTX. MRI of the SPIO and SPIO-PEG-CTX solutions at a different concentration was performed with a 3.0-T MRI scanner (Philips Achieva 3.0T X Series; Phillips Healthcare, The Netherlands). Rabbit VX2 hepatocarcinoma was established by a traditional laparotomy method (injection of the tumor particles into the liver using a 15G syringe needle) following approval by the institutional animal care and use committee. Contrast-enhanced MRI of VX2 rabbits (n=8) was performed using the same MRI scanner with SPIO­PEG-CTX solutions as the contrast agent. Data were analyzed with calibration curve and a paired t-test. The SPIO-PEG-CTX nanoparticles were successfully prepared. With increasing concentrations of the solutions, the MRI signal intensity was increased at T1WI, but decreased at T2WI, which were the same as that for SPIO. Rabbit VX2 carcinoma appeared as a low MRI signal at T1WI, and high at T2WI. After injection of the contrast agent, the MRI signal of carcinoma was decreased relative to that before injection at T2WI (1,161±331.5 vs. 1,346±300.5; P=0.004<0.05), while the signal of the adjacent normal hepatic tissues was unchanged (480.6±165.1 vs. 563.4±67.8; P=0.202>0.05). The SPIO-PEG-CTX nanoparticles showed MRI negative enhancement at T2WI and a targeting effect in liver cancer, which provides the theoretical basis for further study of the early diagnosis of hepatocellular carcinoma.

ChemDes: an integrated web-based platform for molecular descriptor and fingerprint computation.

BACKGROUND: Molecular descriptors and fingerprints have been routinely used in QSAR/SAR analysis, virtual drug screening, compound search/ranking, drug ADME/T prediction and other drug discovery processes. Since the calculation of such quantitative representations of molecules may require substantial computational skills and efforts, several tools have been previously developed to make an attempt to ease the process. However, there are still several hurdles for users to overcome to fully harness the power of these tools. First, most of the tools are distributed as standalone software or packages that require necessary configuration or programming efforts of users. Second, many of the tools can only calculate a subset of molecular descriptors, and the results from multiple tools need to be manually merged to generate a comprehensive set of descriptors. Third, some packages only provide application programming interfaces and are implemented in different computer languages, which pose additional challenges to the integration of these tools. RESULTS: A freely available web-based platform, named ChemDes, is developed in this study. It integrates multiple state-of-the-art packages (i.e., Pybel, CDK, RDKit, BlueDesc, Chemopy, PaDEL and jCompoundMapper) for computing molecular descriptors and fingerprints. ChemDes not only provides friendly web interfaces to relieve users from burdensome programming work, but also offers three useful and convenient auxiliary tools for format converting, MOPAC optimization and fingerprint similarity calculation. Currently, ChemDes has the capability of computing 3679 molecular descriptors and 59 types of molecular fingerprints. CONCLUSION: ChemDes provides users an integrated and friendly tool to calculate various molecular descriptors and fingerprints. It is freely available at http://www.scbdd.com/chemdes. The source code of the project is also available as a supplementary file. Graphical abstract:An overview of ChemDes. A platform for computing various molecular descriptors and fingerprints.

Computational Prediction of DrugTarget Interactions Using Chemical, Biological, and Network Features.

Drugtarget interactions (DTIs) are central to current drug discovery processes. Efforts have been devoted to the development of methodology for predicting DTIs and drugtarget interaction networks. Most existing methods mainly focus on the application of information about drug or protein structure features. In the present work, we proposed a computational method for DTI prediction by combining the information from chemical, biological and network properties. The method was developed based on a learning algorithm-random forest (RF) combined with integrated features for predicting DTIs. Four classes of drugtarget interaction networks in humans involving enzymes, ion channels, G-protein-coupled receptors (GPCRs) and nuclear receptors, are independently used for establishing predictive models. The RF models gave prediction accuracy of 93.52 %, 94.84 %, 89.68 % and 84.72 % for four pharmaceutically useful datasets, respectively. The prediction ability of our approach is comparative to or even better than that of other DTI prediction methods. These comparative results demonstrated the relevance of the network topology as source of information for predicting DTIs. Further analysis confirmed that among our top ranked predictions of DTIs, several DTIs are supported by databases, while the others represent novel potential DTIs. We believe that our proposed approach can help to limit the search space of DTIs and provide a new way towards repositioning old drugs and identifying targets.

Percutaneous transhepatic portal catheterization guided by ultrasound technology for islet transplantation in rhesus monkey.

BACKGROUND: Pig islet xenotransplantation has the potential to overcome the shortage of donated human islets for islet cell transplantation in type 1 diabetes. Testing in non-human primate models is necessary before clinical application in humans. Intraportal islet transplantation in monkeys is usually performed by surgical infusion during laparotomy or laparoscopy. In this paper, we describe a new method of percutaneous transhepatic portal catheterization (PTPC) as an alternative to current methods of islet transplantation in rhesus monkeys. METHODS: We performed ultrasound-guided PTPC in five adult rhesus monkeys weighing 7-8 kg, with portal vein catheterization confirmed by digital subtraction angiography. We monitored for complications in the thoracic and abdominal cavity. To evaluate the safety of ultrasound-guided PTPC, we recorded the changes in portal pressure throughout the microbead transplantation procedure. RESULTS: Ultrasound-guided PTPC and infusion of 16 000 microbeads/kg body weight into the portal vein was successful in all five monkeys. Differences in the hepatobiliary anatomy of rhesus monkeys compared to humans led to a higher initial complication rate. The first monkey died of abdominal hemorrhage 10 hours post-transplantation. The second suffered from a mild pneumothorax but recovered fully after taking only conservative measures. After gaining experience with the first two monkeys, we decreased both the hepatic puncture time and the number of puncture attempts required, with the remaining three monkeys experiencing no complications. Portal pressures initially increased proportional to the number of transplanted microbeads but returned to pre-infusion levels at 30 minutes post-transplantation. The changes in portal pressures occurring during the procedure were not significantly different. CONCLUSIONS: Ultrasound-guided PTPC is an effective, convenient, and minimally invasive method suitable for use in non-human primate models of islet cell transplantation provided that care is taken with hepatic puncture. Its advantages must be weighed against the risks of procedure-related complications.

[Expression of Sema4D in patients with cerebral infarction and its clinical significance].

OBJECTIVE: To explore the expression and clinical significance of Semaphorin4D (Sema4D) mRNA in peripheral blood lymphocyte, Sema4D on platelet surface, soluble Sema4D (sSema4D) in plasma in patients with cerebral infarction. METHODS: Taking 299 patients with cerebral infarction as the case group while 195 healthy adults as the control group. The mRNA expression of Sema4D was detected by Real-time PCR, and Sema4D expression on platelet by flow cytometry, sSema4D by ELISA. Then, the expression of Sema4D on platelet surface and the concentration of sSema4D in plasma of the 195 selected patients following 2 weeks' treatment were tested. RESULTS: The expression of Sema4D mRNA significantly increased in the case group \[(2.23, 2.66)×10(4) IU/ml\] than in the control group \[(0.49, 0.53)×10(4)IU/ml\] (P < 0.01). The level of Sema4D on platelet surface in the case group (191.62 ± 46.56) significantly decreased than in the control group (303.33 ± 112.66) (P < 0.01). But the concentration of sSema4D in plasma in the case group \[(1.34 ± 0.56) µg/L\] was obviously higher than in the control group \[(0.61 ± 0.31) µg/L\] (P < 0.01). The expression of Sema4D on platelet was obviously relevant with the concentration of sSema4D in plasma in the case group with the correlation coefficient as 0.328 (P < 0.01). The expression of Sema4D on platelet obviously peaked up following 2 weeks' routine therapy in the case group, which was close to that in the control group. Meanwhile the concentration of sSema4D in plasma was downward corrected to the normal in the case group. CONCLUSION: The increased expressions and plasma levels, and reduced expressions on platelet of Sema4D in acute period, which returned to normal 2 weeks after treatment in the case group may be related to the occurrence of acute cerebral infarction, reflecting the development process of cerebral infarction.

Kinetics of vascular targeted monoclonal antibody.

PURPOSE: There is growing interest in delivery of drugs and radioisotopes with carriers designed to target molecular receptors in the vascular space. In contrast to targets outside of blood vessels, vascular receptors are easily accessed and tracer binding is not significantly impacted by the size of the targeted drug carrier. Although it is accepted that vascular targeting is very efficient, the kinetics of target binding in the vascular space immediately after injection has not been evaluated. MAb 201B accumulation in mouse lung, by virtue of its binding to thrombomodulin on lung endothelium, has been used as a model for imaging and vascular targeting. PROCEDURES: MAb 201B was radioiodinated with either (125)I comparing two different methods of radioiodination to assess label stability. MAb accumulation and retention were monitored after iv injection in normal BALB/c mice by standard biodistribution experiments, SPECT/CT. MAb radiolabeled with positron emitting (124)I was evaluated by dynamic microPET. RESULTS: The data show that lung uptake and kinetics of loss (t1/2≈40 hrs) of (125)I MAb 201B was similar with two different radio-iodination methods. Loss of radioiodine was detected in sample radiolabeled using the chloramines T method, but only at later time points(24hrs). For very short time evaluations the more efficient chloramine T method was adopted for PET studies with (124)I. Lung uptake of (124)I MAb 201B occurred within seconds of injection as observed in dynamic microPET analysis with little (124)I MAb ever detected in the peripheral circulation. In contrast, distribution kinetics of control (124)I MAb 14 or (124)I MAb 201B that had been diluted with excess cold MAb demonstrated equilibration throughout the vascular space. CONCLUSION: Accumulation of MAb targeted to epitopes in the vascular space occurs very rapidly, is highly specific and very efficient. Drug delivery with vascular targeting agents can accommodate fast acting therapeutic agents including short half lived radioisotopes.