Two-Level Graph Neural Network.

Graph neural networks (GNNs) are recently proposed neural network structures for the processing of graph-structured data. Due to their employed neighbor aggregation strategy, existing GNNs focus on capturing node-level information and neglect high-level information. Existing GNNs, therefore, suffer from representational limitations caused by the local permutation invariance (LPI) problem. To overcome these limitations and enrich the features captured by GNNs, we propose a novel GNN framework, referred to as the two-level GNN (TL-GNN). This merges subgraph-level information with node-level information. Moreover, we provide a mathematical analysis of the LPI problem, which demonstrates that subgraph-level information is beneficial to overcoming the problems associated with LPI. A subgraph counting method based on the dynamic programming algorithm is also proposed, and this has the time complexity of O(n³), where n is the number of nodes of a graph. Experiments show that TL-GNN outperforms existing GNNs and achieves state-of-the-art performance.

Switchable wettability of grain-stacked filter layers from polyurethane plastic waste for oil/water separation.

HYPOTHESIS: Polyurethane plastic waste (PUPW), a port-abundant solid waste, is difficult to degrade naturally and poses a severe threat to the environment. Hence, the effective recycling of PUPW remains a challenge. EXPERIMENTS: Herein, a strategy of converting PUPW into stacked oil/water filtration layer grain through a layer-by-layer (LBL) assembly process is investigated. Notably, such PU-based, grain-stacked, and switchable wettability of the oil/water filter layer is first reported. FINDINGS: The grain-stacked filter layers are flexible for separating immiscible oil/water mixtures, water-in-oil emulsions (WOE), and oil-in-water emulsions (OWE) under gravity over 10 cycle-usages. They can withstand strong acid/alkali solutions (pH = 1-14) and salt solutions over 12 h. Besides, 100-times scale-up experiments have indicated that the obtained filter layers exhibit an upper to 98.2 % separation efficiency for 10 L real industrial oil/water emulsion in the 24 h continuous operation. The demulsification mechanism for emulsions is that the electrostatic interaction along with adsorption between emulsion droplets and grains leads to the uneven distribution of surfactants on the interface film of the emulsion droplets, increasing the probability of tiny droplets colliding and coalescing into large droplets to achieve oil/water separation. This work proposes an effective and economical method of abundant plastic waste for industrial-scale oil-water separation rather than just on the laboratory-scale.

A novel application of pulmonary transit time to differentiate between benign and malignant pulmonary nodules using myocardial contrast echocardiography.

Malignant pulmonary nodules (PNs) are often accompanied by vascular dilatation and structural abnormalities. Pulmonary transit time (PTT) measurement by contrast echocardiograghy has used to assess the cardiopulmonary function and pulmonary vascular status, such as hepatopulmonary syndrome and pulmonary arteriovenous fistula, but has not yet been attempted in the diagnosis and differential diagnosis of PNs. The aim of this work was to evaluate the feasibility and performance of myocardial contrast echocardiography (MCE) for differentiating malignant PNs from benign ones. The study population consisted of 201 participant: 66 healthy participants, 65 patients with benign PNs and 70 patients with malignant PNs. Their clinical and conventional echocardiographic characteristics were collected. MCE with measurements of PTT were performed. There was no difference in age, sex, heart rate, blood pressure, smoking rate, background lung disease, pulmonary function, ECG, myocardial enzymes, cardiac size and function among the healthy participant, patients with benign and malignant PNs (P > 0.05). PTT did not differ significantly in patients with PNs of different sizes, nor did they differ in patients with PNs of different enhancement patterns (P > 0.05). However, the PTT were far shorter (about one half) in patients with malignant PNs than in patients with benign ones (1.88 ± 0.37 vs. 3.73 ± 0.35, P < 0.001). There was no significantly different between patients with benign PNs and healthy participant (3.73 ± 0.35 vs.3.89 ± 0.36, P > 0.05). The area under the receiver operating characteristics curve (AUC) of PTT was 0.99(0.978-1.009) in discriminating between benign and malignant PNs. The optimal cutoff value was 2.78 s, with a sensitivity of 98.52%, a specificity of 97.34%, and a accuracy of 97.69%. MCE had a powerful performance in differentiating between benign and malignant PNs, and a pulmonary circulation time of < 2.78 s indicated malignant PNs.

Transition-Metal Free Chemoselective Hydroxylation and Hydroxylation-Deuteration of Heterobenzylic Methylenes.

We developed an approach for direct selective hydroxylation of heterobenzylic methylenes to secondary alcohols avoiding overoxidation to ketones by using a KOBu-t/DMSO/air system. Most reactions could reach completion in several minutes to give hydroxylated products in 41-76% yields. Using DMSO-d6, this protocol resulted in difunctionalization of heterobenzylic methylenes to afford α-deuterated secondary alcohols (>93% incorporation). By employing this method, active pharmaceutical ingredients carbinoxamine and doxylamine were synthesized in two steps in moderate yields.

Acetylresveratrol as a Potential Substitute for Resveratrol Dragged the Toxic Aldehyde to Inhibit the Mutation of Mitochondrial DNA.

The aim of this study was to explore whether or not acetylresveratrol as a potential substitute for resveratrol dragged the toxic aldehyde to inhibit the mutation of mitochondrial DNA. The results revealed that the acetylresveratrol shifted ultraviolet peak of trans-crotonaldehyde from 316 to 311 nm. In mitochondria, the acetylresveratrol split the ultraviolet peak at 311 nm of trans-crotonaldehyde into 311 nm and 309 nm; the aldehyde Raman band of trans-crotonaldehyde was red shifted by the acetylresveratrol from 1689 to 1686 cm-1 with obvious band decline; Raman bands at 1149 cm-1, 1168 cm-1, and 1325 cm-1 of acetylresveratrol disappeared. In aldehyde dehydrogenase, the aldehyde Raman band of trans-crotonaldehyde was red shifted by the acetylresveratrol from 1689 to 1684 cm-1 with band decline; Raman bands at 1150 cm-1, 1168 cm-1, and 1324 cm-1 of acetylresveratrol declined. The weak acidic microenvironment was the best, for the acetylresveratrol dragged the toxic aldehyde of trans-crotonaldehyde. Compared with the resveratrol, the effect of the acetylresveratrol on the toxic aldehyde of trans-crotonaldehyde was very similar to that of the resveratrol. The acetylresveratrol is very suitable as a potential substitute for resveratrol dragged the toxic aldehyde to inhibit the mutation of mitochondrial DNA. Graphical Abstract In mitochondria, the Raman band of the toxic -CH=O of trans-crotonaldehyde (TCA) dragged by the Acetyl-Res from 1689 to 1686 cm-1 with obvious band decline, while the Raman bands at 1149 cm-1, 1168 cm-1, and 1325 cm-1 of the Acetyl-Res disappeared, respectively. The Acetyl-Res is very suitable as a potential substitute, for the Res dragged the toxic -CH=O of TCA to inhibit the mutation of mitochondrial DNA for anticancer.

Copper Promoted Aerobic Oxidative C(sp3)-C(sp3) Bond Cleavage of N-(2-(Pyridin-2-yl)-ethyl)anilines.

A strategy of aerobic oxidative C(sp3)-C(sp3) bond cleavage of N-ethylaniline derivatives bearing azaarenes for the synthesis of N-aryl formamides has been developed. This approach was carried out smoothly with the CuI/TEMPO/air system to give N-aryl formamides in yields of 50-90%. With this methodology, a mutagenically active compound was constructed in 90% yield. Moreover, the reaction also provided a one-pot synthetic tool for accessing a promoter of hematopoietic stem cells by difunctionalization in 61% yield.

Systemic immunization with altered myelin basic protein peptide produces sustained antidepressant-like effects.

Immune dysregulation, specifically of inflammatory processes, has been linked to behavioral symptoms of depression in both human and rodent studies. Here, we evaluated the antidepressant effects of immunization with altered peptide ligands of myelin basic protein (MBP)-MBP87-99[A91, A96], MBP87-99[A91], and MBP87-99[R91, A96]-in different models of depression and examined the mechanism by which these peptides protect against stress-induced depression. We found that a single dose of subcutaneously administered MBP87-99[A91, A96] produced antidepressant-like effects by decreasing immobility in the forced swim test and by reducing the escape latency and escape failures in the learned helplessness paradigm. Moreover, immunization with MBP87-99[A91, A96] prevented and reversed depressive-like and anxiety-like behaviors that were induced by chronic unpredictable stress (CUS). However, MBP87-99[R91, A96] tended to aggravate CUS-induced anxiety-like behavior. Chronic stress increased the production of peripheral and central proinflammatory cytokines and induced the activation of microglia in the prelimbic cortex (PrL), which was blocked by MBP87-99[A91, A96]. Immunization with MBP-derived altered peptide ligands also rescued chronic stress-induced deficits in p11, phosphorylated cyclic adenosine monophosphate response element binding protein, and brain-derived neurotrophic factor expression. Moreover, microinjections of recombinant proinflammatory cytokines and the knockdown of p11 in the PrL blunted the antidepressant-like behavioral response to MBP87-99[A91, A96]. Altogether, these findings indicate that immunization with altered MBP peptide produces prolonged antidepressant-like effects in rats, and the behavioral response is mediated by inflammatory factors (particularly interleukin-6), and p11 signaling in the PrL. Immune-neural interactions may impact central nervous system function and alter an individual's response to stress.

Toxic trans-crotonaldehyde in mitochondria intercepted by oxyresveratrol contributing to anticancer.

The aim of this study was to explore how the toxic trans-crotonaldehyde (TCA) in mitochondria or aldehyde dehydrogenase (ALDH) at different pHs was intercepted by oxyresveratrol (Oxy-Res) contributing to anticancer. Ultraviolet-visible (UV-vis) spectroscopy and Raman spectroscopy were employed. UV-vis spectra showed that the Oxy-Res red shifted the peak of the toxic TCA from 316 nm to 325 nm, while the peaks of the Oxy-Res shifted from 329 nm with 290 nm and 300 nm to 325 nm with 303 nm. In the mitochondria, the Oxy-Res blue shifted the peaks of the toxic TCA from 325 nm with 303 nm to 321 nm with 301 nm. Raman spectra revealed that the Oxy-Res caused shifting of the CHO of the toxic TCA from 1,689 cm-1 to 1,671 cm-1 with band decline. The CC of the toxic TCA at 1641 cm-1 was split into 1,639 cm-1 and 1,642 cm-1 with band decline. The bands of the Oxy-Res at 1634 cm-1 , 1,617 cm-1 , and 1,595 cm-1 disappeared. In the mitochondria, the CC of the toxic TCA at 1641 cm-1 splitting disappeared. In ALDH, with the decrease of pH from 7.8 to 6.5, the CHO of the toxic TCA did not red shift from 1,689 cm-1 to 1,674 cm-1 up to pH 6.5. There was no change in the CC of the toxic TCA at 1640 cm-1 in ALDH at different pHs. The conclusion of the study was that the CHO of the toxic TCA was intercepted by the Oxy-Res under the action of ALDH in the mitochondria, particularly at pH 7.8. © 2019 IUBMB Life, 2019.

Correction: EphB2 in the medial prefrontal cortex regulates vulnerability to stress.

Following publication of the above article, the authors noticed that an incorrect version of Figs. 2f, 3f, 5h and 7d was presented.

Downregulation of ENDOCAN in myeloid leukemia cells inhibits proliferation and promotes apoptosis by suppressing nuclear factor­κB activity.

Previous studies have demonstrated that ENDOCAN is elevated in leukemia, and it has been reported to be associated with poor prognosis. However, the functional role of ENDOCAN in the development of leukemia remains to be fully elucidated. In the present study, the expression levels of ENDOCAN were detected in THP­1, U937, HL­60 and K562 cells, and it was found that ENDOCAN was increased in U937 and K562 cells, compared with the other two cell lines. Subsequently, ENDOCAN was knocked down in U937 and K562 cells via lentiviral infection. It was found that cell proliferation and the expression of proliferating cell nuclear antigen were inhibited in myeloid leukemia cells following the silencing of ENDOCAN. ENDOCAN knockdown induced G0/G1­phase cell cycle arrest in myeloid leukemia cells with a decreased expression of cyclin D1. Furthermore, cell apoptosis was increased in response to ENDOCAN silencing, which was accompanied by the downregulation of B­cell lymphoma (BCL2) and the upregulation of BCL2­associated X protein, cleaved caspases 3 and 9, and cleaved poly (ADP­ribose) polymerase. Furthermore, it was demonstrated that the knockdown of ENDOCAN inhibited nuclear factor­κB (NF­κB) activity, as evidenced by the increased expression of NF­κB inhibitor α (IκBα), decreased expression of phosphorylated (p­)IκBα, p­P65 and nuclear P65, and reduced NF­κB DNA­binding activity. In combination, the present findings suggested that ENDOCAN may serve as a potential therapeutic target in the treatment of leukemia.

Synthesis and Structure-Activity Relationships of 4-Morpholino-7,8-Dihydro-5H-Thiopyrano[4,3-d]pyrimidine Derivatives Bearing Pyrazoline Scaffold.

Phosphatidylinositol 3-kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway is abnormally active in the growth and proliferation of cancer cells. The inhibition of PI3K kinase can effectively block the conduction of signaling pathways and is an ideal target for drug design. In this paper; two series of 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing pyrazoline moiety (7a-l; 8a-l) were synthesized; and their cytotoxicity in vitro were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method against four human cancer cell lines including A549; PC-3; MCF-7; and HepG2 cell lines. The activity of the most promising compound 8d against PI3Kα kinase was further evaluated. The results indicated that most of the target compounds showed moderate to excellent cytotoxicity and the most promising compound 8d showed excellent cytotoxicity against four cancer cell lines with half maximal inhibitory concentration (IC50) values of 6.02-10.27 µM. In addition; the compound 8d was found to have a moderate inhibitory activity in the PI3Kα enzyme assay. What's more; the compounds of which the substituents of benzene ring at the C-4 position are electron-withdrawing groups such as substituents (Cl; F; Br) have better activity than the compounds containing the electron donating groups (OCH3; H). However; the exact action mechanism is not quite clear right now. Further study will be carried out to identify the exact target in near future.

Malignancy risk stratification of thyroid nodules: comparisons of four ultrasound Thyroid Imaging Reporting and Data Systems in surgically resected nodules.

To compare the efficiency of four different ultrasound (US) Thyroid Imaging Reporting and Data Systems (TI-RADS) in malignancy risk stratification in surgically resected thyroid nodules (TNs). The study included 547 benign TNs and 464 malignant TNs. US images of the TNs were retrospectively reviewed and categorized according to the TI-RADSs published by Horvath E et al. (TI-RADS H), Park et al. (TI-RADS P), Kwak et al. (TI-RADS K) and Russ et al. (TI-RADS R). The diagnostic performances for the four TI-RADSs were then compared. At multivariate analysis, among the suspicious US features, marked hypoechogenicity was the most significant independent predictor for malignancy (OR: 15.344, 95% CI: 5.313-44.313) (P < 0.05). Higher sensitivity was seen in TI-RADS H, TI-RADS K, TI-RADS R comparing with TI-RADS P (P < 0.05 for all), whereas the specificity, accuracy and area under the ROC curve (Az) of TI-RADS P were the highest (all P < 0.05). Higher specificity, accuracy and Az were seen in TI-RADS K compared with TI-RADS R (P = 0.003). With its higher sensitivity, TI-RADS K, a simple predictive model, is practical and convenient for the management of TNs in clinical practice. The study indicates that there is a good concordance between TI-RADS categories and histopathology.

Predictable Chronic Mild Stress during Adolescence Promotes Fear Memory Extinction in Adulthood.

Early-life stress in adolescence has a long-lasting influence on brain function in adulthood, and it is mostly recognized as a predisposing factor for mental illnesses, such as anxiety and posttraumatic stress disorder. Previous studies also indicated that adolescent predictable chronic mild stress (PCMS) in early life promotes resilience to depression- and anxiety-like behaviors in adulthood. However, the role of PCMS in associated memory process is still unclear. In the present study, we found that adolescent PCMS facilitated extinction and inhibited fear response in reinstatement and spontaneous recovery tests in adult rats, and this effect was still present 1 week later. PCMS in adolescence increased the activity of brain-derived neurotrophic factor (BDNF)-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in infralimbic cortex (IL) but not prelimbic cortex in adulthood. Intra-IL infusion of BDNF antibody and the ERK1/2 inhibitor U0126 reversed PCMS-induced enhancement of fear extinction. Moreover, we found that PCMS decreased DNA methylation of the Bdnf gene at exons IV and VI and elevated the mRNA levels of Bdnf in the IL. Our findings indicate that adolescent PCMS exposure promotes fear memory extinction in adulthood, which reevaluates the traditional notion of adolescent stress.

Synthesis and Biological Evaluation of Novel 8-Morpholinoimidazo[1,2-a]pyrazine Derivatives Bearing Phenylpyridine/Phenylpyrimidine-Carboxamides.

Herein we designed and synthesized three series of novel 8-morpholinoimidazo[1,2-a]pyrazine derivatives bearing phenylpyridine/phenylpyrimidine-carboxamides (compounds 12a-g, 13a-g and 14a-g). All the compounds were evaluated for their IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Most of the target compounds exhibited moderate cytotoxicity against the three cancer cell lines. Two selected compounds 14b, 14c were further tested for their activity against PI3Kα kinase, and the results indicated that compound 14c showed inhibitory activity against PI3Kα kinase with an IC50 value of 1.25 µM. Structure-activity relationships (SARs) and pharmacological results indicated that the replacement of the thiopyranopyrimidine with an imidazopyrazine was beneficial for the activity and the position of aryl group has a significant influence to the activity of these compounds. The compounds 13a-g in which an aryl group substituted at the C-4 position of the pyridine ring were more active than 12a-g substituted at the C-5 position. Moreover, the cytotoxicity of compounds 14a-g bearing phenylpyrimidine-carboxamides was better than that of the compounds 12a-g, 13a-g bearing phenylpyridine-carboxamides. Furthermore, the substituents on the benzene ring also had a significant impact on the cytotoxicity and the pharmacological results showed that electron donating groups were beneficial to the cytotoxicity.

Virtual touch tissue imaging and quantification (VTIQ) in the evaluation of thyroid nodules: the associated factors leading to misdiagnosis.

To evaluate the associated factors leading to misdiagnosis with VTIQ for differentiation between benign from malignant thyroid nodules (TNs). The study included 238 benign TNs and 150 malignant TNs. Conventional ultrasound (US) features and VTIQ parameters were obtained and compared with the reference standard of histopathological and/or cytological results. Binary logistic regression analysis was performed to select independent variables leading to misdiagnosis. The maximum shear wave speed (SWS) (SWS-max), mean SWS (SWS-mean), SWS-ratio and standard deviation of SWS (SWS-SD) were significantly higher for malignant TNs compared with benign TNs (all P < 0.001). SWS-mean achieved the highest diagnostic performance with a cut-off value of 3.15 m/s. False positive rate was 13.4% (32/238) while false negative rate was 35.3% (53/150). Intranodular calcification (OR: 1.715) was significantly associated with false positive VTIQ findings, while nodule size (OR: 0.936) and echotexture of the thyroid gland (OR: 0.033) were negatively associated with them. Nodule depth (OR: 0.881) and TI-RADS category (OR: 0.563) were negatively associated with false negative VTIQ findings. These US characteristic of TNs should be taken into consideration when interpreting the results of VTIQ examinations.

Risk stratification of thyroid nodules with Bethesda category III results on fine-needle aspiration cytology: The additional value of acoustic radiation force impulse elastography.

To assess the value of conventional ultrasound, conventional strain elastography (CSE) and acoustic radiation force impulse (ARFI) elastography in differentiating likelihood of malignancy for Bethesda category III thyroid nodules. 103 thyroid nodules with Bethesda category III results on fine-needle aspiration cytology (FNAC) in 103 patients were included and all were pathologically confirmed after surgery. Conventional ultrasound, CSE and ARFI elastography including ARFI imaging and point shear wave speed (SWS) measurement were performed. Univariate and multivariate analyses were performed to identify the independent factors associated with malignancy. Area under the receiver operating characteristic curve (Az) was calculated to assess the diagnostic performance. Pathologically, 65 nodules were benign and 38 were malignant. Significant differences were found between benign and malignant nodules in ARFI. The cut-off points were ARFI imaging grade ≥ 4, SWS > 2.94 m/s and SWS ratio > 1.09, respectively. ARFI imaging (Az: 0.861) had the highest diagnostic performance to differentiate malignant from benign nodules, following by conventional ultrasound (Az: 0.606 - 0.744), CSE (Az: 0.660) and point SWS measurement (Az: 0.725 - 0.735). Multivariate logistic regression analysis showed that ARFI imaging grade ≥ 4 was the most significant independent predictor. The combination of ARFI imaging with point SWS measurement significantly improved the specificity (100% vs. 80.0%) and positive predictive value (100 % vs. 72.9%) in comparison with ARFI imaging alone. ARFI elastography is a useful tool in differentiating malignant from benign thyroid nodules with Bethesda category III results on FNAC.

BDNF-GSK-3ß-ß-Catenin Pathway in the mPFC Is Involved in Antidepressant-Like Effects of Morinda officinalis Oligosaccharides in Rats.

Background: Morinda officinalis oligosaccharides have been reported to exert neuroprotective and antidepressant-like effects in the forced swim test in mice. However, the mechanisms that underlie the antidepressant-like effects of Morinda officinalis oligosaccharides are unclear. Methods: Chronic unpredictable stress and forced swim test were used to explore the antidepressant-like effects of Morinda officinalis oligosaccharides and resilience to stress in rats. The phosphoinositide-3 kinase inhibitor LY294002 was microinjected in the medial prefrontal cortex to explore the role of glycogen synthase kinase-3ß in the antidepressant-like effects of Morinda officinalis oligosaccharides. The expression of brain-derived neurotrophic factor, phosphorylated-Ser9-glycogen synthase kinase 3ß, ß-catenin, and synaptic proteins was determined in the medial prefrontal cortex and the orbitofrontal cortex by western blot. Results: We found that Morinda officinalis oligosaccharides effectively ameliorated chronic unpredictable stress-induced depression-like behaviors in the sucrose preference test and forced swim test. The Morinda officinalis oligosaccharides also significantly rescued chronic unpredictable stress-induced abnormalities in the brain-derived neurotrophic factor-glycogen synthase kinase-3ß-ß-catenin pathway and synaptic protein deficits in the medial prefrontal cortex but not orbitofrontal cortex. The activation of glycogen synthase kinase-3ß by the phosphoinositide-3 kinase inhibitor LY294002 abolished the antidepressant-like effects of Morinda officinalis oligosaccharides in the forced swim test. Naïve rats that were treated with Morinda officinalis oligosaccharides exhibited resilience to chronic unpredictable stress, accompanied by increases in the expression of brain-derived neurotrophic factor, phosphorylated-Ser9-glycogen synthase kinase-3ß, and ß-catenin in the medial prefrontal cortex. Conclusion: Our findings indicate that the brain-derived neurotrophic factor-glycogen synthase kinase-3ß-ß-catenin pathway in the medial prefrontal cortex may underlie the antidepressant-like effect of Morinda officinalis oligosaccharides and resilience to stress.

Synthesis and Biological Evaluation of Novel 4-Morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine Derivatives Bearing Phenylpyridine/ Phenylpyrimidine-Carboxamides.

Four series of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives 11a-j, 12a-j, 13a-g and 14a-g bearing phenylpyridine/phenylpyrimidine- carboxamide scaffolds were designed, synthesized and their IC50 values against three cancer cell lines (A549, PC-3 and MCF-7) were evaluated. Eleven of the compounds showed moderate cytotoxicity activity against the cancer cell lines. Structure-activity relationships (SARs) and pharmacological results indicated that the introduction of phenylpyridine-carboxamide scaffold was beneficial for the activity. What's more, the oxidation of the sulfur atom in thiopyran and various types of substituents on the aryl group have different impacts on different series of compounds. Furthermore, the positions of aryl group substituents have a slight impact on the activity of the phenylpyridine-carboxamide series compounds.

Synthesis and anticancer activity of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety.

Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety (10a-j, 13a-j). All the compounds were evaluated for the IC50 values against five cancer cell lines (A549, PC-3, MCF-7, Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3Kα kinase in further. The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Kα kinase and five cancer cell lines with IC50 values of 1.1µM, 0.92µM and 8.77-14.3µM. Structure-activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities.

Design, synthesis, biological evaluation and docking studies of novel 2-substituted-4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives as dual PI3Kα/mTOR inhibitors.

Four series of 2-substituted-4-morpholino- 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives (9-28) were designed, synthesized and their structures were confirmed by (1)H NMR, (13)C NMR and MS spectrum. All compounds were evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). And four selected compounds (10, 11, 24, 27) were further evaluated for the IC50 values against PI3Kα and mTOR kinases. Seven of the target compounds exhibited moderate to excellent antitumor activities against these three cancer cell lines. The most promising compound 11 showed good antitumor potency for A549, PC-3 and MCF-7 cell lines with IC50 values of 0.52 ± 0.10 µM, 1.41 ± 0.10 µM, 4.82 ± 0.24 µM and moderate antitumor activities against PI3Kα/mTOR with IC50 values of 6.72 ± 0.30 µM and 0.94 ± 0.10 µM. Structure-activity relationships (SARs) and docking studies indicated that aryl urea scaffolds had a significant impact on the antitumor activities, and aryl pyridine urea scaffolds produced the best potency. Variations in substitutions of the aryl group had a significant impact on the activity and 3-Cl-4-F or 3-CF3-4-Cl substitution was more preferred.