Novel compound ZCJ14, a gefitinib analog, exhibited prominent anti-cancer effect among several cancer cell lines.

AIM: ZCJ14, a gefitinib analog, exhibited prominent anti-cancer effect both in vitro and in vivo. The present study aims to investigate the inhibitory effects of ZCJ14 on human cancer cells, and explored its possible mechanism of action. MAIN METHODS: The inhibitory effect of ZCJ14 on human-derived tumor cells in vitro was mainly measured by MTT and colony formation assays. The nude mouse xenograft models were established to figure out the inhibitory effect of ZCJ14 on solid tumors in vivo. Western blotting assays were used to detect the phosphorylation level of EGFR down-streaming proteins and the proteomic technique was used to study the proteome alterations of cancer cells triggered by ZCJ14. KEY FINDINGS: ZCJ14 inhibited the proliferation of A549 (lung cancer), HCT116 (colorectal cancer) and MCF-7 (breast cancer) cells in vitro with 48 h IC50 values of 0.83, 0.85 and 0.92 µM, respectively. It suppressed the growth of A549, NCI-H1975, NCI-H1299 and MCF-7, HCT116 tumors in mouse xenograft models, and had almost no toxicity. At the same dose, the inhibitory effect of ZCJ14 on solid tumors was better than the corresponding positive drugs. ZCJ14 does not exert anti-tumor effects through inhibition of EGFR pathway, but by enhancing steroid biosynthesis and inhibiting ubiquitin-mediated proteolysis. SIGNIFICANCE: Based on the excellent anti-tumor effect of ZCJ14 on human tumor cell lines, it can be used as an effective anti-tumor drug candidate. In addition, the results of proteomic study in this paper can provide clues for further study of the anti-tumor mechanism of ZCJ14.

Structural modification and antihypertensive activity study of formononetin derivatives.

A series of formononetin derivatives with substituted benzyloxy groups on the 4' position of isoflavone were designed and synthesized. Their vasodilative activities were evaluated by wire myograph system on isolated rat mesenteric arterial ring. The preliminary SAR of target compounds was thus discussed. Compounds 3d and 3e exhibited potent vasodilative activities against the rat mesenteric arterial rings induced contraction with K+. Compounds 3d and 3e also showed antihypertensive effects in SHRs by oral administration.

Quantitative analysis and pharmacokinetic study of a novel diarylurea EGFR inhibitor (ZCJ14) in rat plasma using a validated LC-MS/MS method.

1-(4-(Pyrrolidin-1-yl-methyl)phenyl)-3-(4-((3-(trifluoromethyl) phenyl)amino)quinazolin-6-yl)urea (ZCJ14), a novel epidermal growth factor receptor (EGFR) inhibitor, with diarylurea moiety, displays anticancer effect. In the present study, an LCMS/MS method was established to determine the concentration of ZCJ14 in rat plasma. Furthermore, the method was applied to investigate the pharmacokinetic characteristics of ZCJ14. Chromatographic separation of ZCJ14 and internal standard (IS) [1-phenyl-3-(4-((3-(trifluoromethyl)phenyl)amino) quinazolin-6-yl)urea] was accomplished by gradient elution using the Kromasil C18 column. The selected reaction monitoring transitions were performed at m/z 507.24→436.18 and 424.13→330.96 for ZCJ14 and IS, resp. The established method was linear over the concentration range of 10-1000 ng mL-1. The intra- and inter-day precisions were < 11.0 % (except for LLOQ which was up to 14.3 %) and the respective accuracies were within the range of 87.5-99.0 %. The extraction recovery and matrix effect were within the range of 88.4-104.5 % and 87.3-109.9 %, resp. ZCJ14 was stable under all storage conditions. The validated method was successfully applied to the pharmacokinetic study of ZCJ14 in rats, and the pharmacokinetic parameters have been determined. The oral bioavailability of ZCJ14 was found to be 46.1 %. Overall, this accurate and reliable quantification method might be useful for other diarylurea moiety-containing drugs.

Cultural Perspectives on Tobacco Use and Cessation Among Chinese American Immigrants: A Community-Engaged Qualitative Study.

INTRODUCTION: Tobacco use is a preventable cause of death among ethnic minorities. Chinese Americans have high smoking rates and underutilize evidence-based cessation therapies. Community members' perspectives on tobacco use and cessation may help bridge treatment gaps and ensure that cessation approaches are aligned with cultural values. METHODS: Focus group methods were used to explore cultural factors influencing tobacco use and cessation among 50 Chinese immigrants. Emerging themes were identified using thematic analysis. RESULTS: The three emerging themes are (a) tobacco use is influenced by Chinese American immigrants' socioecological environment, (b) self-discipline determines the ability to quit, and (c) complex family dynamics influence quitting. DISCUSSION: Cessation approaches framed within cultural perspectives may help bridge treatment gaps. Innovations such as leveraging soft technologies that are widely used in the community may extend the reach of health promotion campaigns and treatments.

Vasodilation and hypotension of a novel 3-benzylquinazolin- 4(3H)-one derivative via the inhibition of calcium flux.

A novel 3-benzylquinazolin-4(3H)-one derivative Z32, namely 6,7-dimethoxy-3-(3-chloro-4-(4-fluorobenzyloxy)benzyl)quinazolin-4(3H)-one was synthesized. The vasorelaxant and antihypertensive effects of Z32 and its underlying mechanisms were investigated. The following methods were used. The isometric tension of artery ring segments was recorded using an in vitro myography system. Changes in the calcium influx in mesenteric arteries were surveyed using a real-time confocal microscopy. The arterial pressure of spontaneously hypertensive rats was measured in vivo using a non-invasive tail cuff blood pressure system. The results showed that Z32 can relax rat mesenteric arteries pre-constricted by KCl or phenylephrine in a concentration-dependent manner. The vasorelaxant effects were not affected by the removal of the endothelium, blockade of potassium channels by tetraethylammonium chloride, or inhibition of either guanylate cyclase by ODQ, nitric oxide synthase by l-NAME, or cyclooxygenase by indomethacin. In Ca2+-free conditions, Z32 did not affect the constriction evoked by caffeine, however, significantly reduced the constrictions induced (1) by phenylephrine, (2) by CaCl2 in either phenylephrine (in the presence of verapamil) or KCl stimulated arteries, (3) by extracellular Ca2+ restoration in thapsigargin-treated mesenteric arteries, and (4) by the activator of protein kinase C phorbol-12, 13-dibutyrate, and the inhibitor of protein tyrosine phosphatase sodium orthovanadate. Further, Z32 decreased the systolic and diastolic arterial pressure of spontaneously hypertensive rats in a dose-dependent manner. In conclusion, Z32 lowers the arterial pressure and induces vasorelaxation through the inhibition of calcium flux, probably via a protein tyrosine phosphorylation-dependent way.

Evaluations of treatment efficacy of depression from perspective of both patients' symptoms and general sense of mental health and wellbeing: A large scale, multi-centered, longitudinal study in China.

Relying on the absence, presence of level of symptomatology may not provide an adequate indication of the effects of treatment for depression, nor sufficient information for the development of treatment plans that meet patients' needs. Using a prospective, multi-centered, and observational design, the present study surveyed a large sample of outpatients with depression in China (n=9855). The 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Remission Evaluation and Mood Inventory Tool (REMIT) were administered at baseline, two weeks later and 4 weeks, to assess patients' self-reported symptoms and general sense of mental health and wellbeing. Of 9855 outpatients, 91.3% were diagnosed as experiencing moderate to severe depression. The patients reported significant improvement over time on both depressive symptoms and general sense after 4-week treatment. The effect sizes of change in general sense were lower than those in symptoms at both two week and four week follow-up. Treatment effects on both general sense and depressive symptomatology were associated with demographic and clinical factors. The findings indicate that a focus on both general sense of mental health and wellbeing in addition to depressive symptomatology will provide clinicians, researchers and patients themselves with a broader perspective of the status of patients.

An HPLC method for the determination of a novel anti-hypertension agent 6,7-dimethoxy-3-(4-(4-fluorobenzyloxy)-3-methoxyphenylmethyl)quinazolin-4(3H)-one in rat plasma: application to pharmacokinetic study.

6,7-dimethoxy-3-(4-(4-fluorobenzyloxy)-3-methoxyphenylmethyl) quinazolin-4(3H)-one (DFMQ-19), a novel analogue of 3-benzylquinazolin-4(3H)-ones, may be considered as a drug candidate for the treatment of hypertension. The aim of this study was to develop and validate a reverse-phase high-performance liquid chromatography to determine the DFMQ-19 in plasma and demonstrate its application in pharmacokinetic study. Separation of DFMQ-19 and I.S (structural analog of DFMQ-19) was performed using Shim-Pack VP-ODS column and a mixture of acetonitrile and water as mobile phase. The HPLC method was validated according to the ICH guidelines. The limit of detection and lower limit of quantitation were 0.05 µg/ml and 0.1 µg/ml respectively. The recovery rate of DFMQ-19 from blood samples was >81% of the spiked amount. The RSD of the intra- and inter-day precisions was within 7.5%, and RE of accuracy was between -14.4% and 4.5%. This method was successfully applied to the pharmacokinetic study after administration of DFMQ-19. The pharmacokinetic parameters, such as half-life (t1/2 ), mean residence time (MRT), maximum concentration (Cmax ) were determined. Based on these pharmacokinetic parameters, the oral bioavailability of DFMQ-19 was calculated to be 13.42% in rat. This article is protected by copyright. All rights reserved. HIGHLIGHTS: HPLC method was validated to quantify DFMQ-19 in rat plasma I.S is one of the structural analogs of the analyte The HPLC method was validated according to the ICH guidelines The oral bioavailability of DFMQ-19 was 13.42% in rat.

Combination of 4-anilinoquinazoline, arylurea and tertiary amine moiety to discover novel anticancer agents.

In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50 mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors.

Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3-substituted quinazolin-4(3H)-one moiety.

In present study, a series of N-(2-methoxy-5-(3-substituted quinazolin-4(3H)-one-6-yl)-pyridin-3-yl)phenylsulfonamide were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against HCT116 and MCF-7 cancer cell lines. The SAR of title compounds was discussed. The compounds (S)-C5 and (S)-C8 displayed potent inhibitory activity against PI3Ks and mTOR, especially against PI3Kα. In addition, compound (S)-C5 can efficaciously inhibit tumor growth in a mice S-180 model. These findings suggest that our designed compounds can serve as potent PI3K inhibitors and effective anticancer agents.

Association between SREBF2 gene polymorphisms and metabolic syndrome in clozapine-treated patients with schizophrenia.

BACKGROUND: Patients with schizophrenia using antipsychotics often develop metabolic side effects, especially with clozapine. Previous studies indicated that antipsychotics could activate the pathway of the sterol regulatory element-binding protein (SREBP). The sterol regulatory element binding transcription factor 2 (SREBF2) gene mainly regulates the cholesterol biosynthetic gene. Therefore, we hypothesized that the SREBF2 gene would be a candidate gene for interindividual variation in drug-induced metabolic syndrome (MetS). In this genetic case-control study, we examined the SREBF2 gene polymorphisms in the risk of MetS patients treated with clozapine. METHODS: Ten single nucleotide polymorphisms (SNPs) of SREBF2 were genotyped in a CHB (Han Chinese in Beijing, China) population, a sample of 621 schizophrenia patients treated with clozapine. Patients were evaluated for metabolic parameters and screened for the MetS criteria. RESULTS: The incidence of MetS among all subjects was 41.8% (260/621). Two markers of SREBF2 were associated with MetS induced by clozapine after False Discovery Rate (FDR) correction (rs1052717, corrected Pallele=0.010, corrected Pgenotype=0.022; and rs2267443, corrected Pgenotype=0.015). Patients who received clozapine and carried the A-allele of rs2267443 or rs1052717 had an increased risk of MetS (rs2267443, odds ratio (OR)=1.67, 95% confidence interval (CI): 1.20-2.34; and rs1052717, OR=1.81, 95% CI: 1.15-1.98), adjusted by logistic regression for clinical characteristics. CONCLUSION: The results suggest that the genetic polymorphisms of SREBF2 gene may be associated with MetS in patients treated with clozapine.

Sleep problems among clinically depressed adults in China.

BACKGROUND: The aim of the study was to explore which variables predict poor sleep among clinically depressed Chinese adults. METHODS: In total, 100 participants were recruited from Shanghai Mental Health Centre. The dependent variables were number of hours spent sleeping as well as the quality of sleep and number of times the participants woke during the night. The independent variables were gender, age, length of depression and severity of depression. The use of antipsychotic medication was controlled for in all analyses. RESULTS: The results demonstrated that depression severity was the most important predictor of sleep quality and night waking. Gender and age were also found to be predictors of sleep problems. CONCLUSIONS: The findings demonstrated that depressed Chinese patients experienced similar relationships between sleep disturbance and depression to Westerners. Future studies should include other measures of sleep quality as well as variables consistently found to be associated with both depression and sleep difficulty, such as the use of addictive substances and psychosocial factors.

Discovery of novel 3-benzylquinazolin-4(3H)-ones as potent vasodilative agents.

In the present study, a series of 3-benzylquinazolin-4(3H)-ones were synthesized and characterized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60mM KCl. The SAR of target compounds was discussed preliminarily. Among these compounds, 2a and 2c displayed potent vasodilatation action and could compete significantly the rat mesenteric arterial rings induced contraction with phenylephrine. Compounds 2a and 2c were further tested for their antihypertensive effects in SHR by oral administration. The results indicated that 2a and 2c could reduce significantly both diastolic and systolic blood pressure. Moreover, 2c displayed antihypertensive effect in a dose dependent manner, and could maintain the effects for 6h at a dosage of 4.0mg/kg. These findings suggest that the title compounds are novel vasodilative agents, representing a novel series of promising antihypertensive agents.

Abnormalities of white matter microstructure in unmedicated obsessive-compulsive disorder and changes after medication.

BACKGROUND: Abnormalities of myelin integrity have been reported in obsessive-compulsive disorder (OCD) using multi-parameter maps of diffusion tensor imaging (DTI). However, it was still unknown to what degree these abnormalities might be affected by pharmacological treatment. OBJECTIVE: To investigate whether the abnormalities of white matter microstructure including myelin integrity exist in OCD and whether they are affected by medication. METHODOLOGY AND PRINCIPAL FINDINGS: Parameter maps of DTI, including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD), were acquired from 27 unmedicated OCD patients (including 13 drug-naïve individuals) and 23 healthy controls. Voxel-based analysis was then performed to detect regions with significant group difference. We compared the DTI-derived parameters of 15 patients before and after 12-week Selective Serotonin Reuptake Inhibitor (SSRI) therapies. Significant differences of DTI-derived parameters were observed between OCD and healthy groups in multiple structures, mainly within the fronto-striato-thalamo-cortical loop. An increased RD in combination with no change in AD among OCD patients was found in the left medial superior frontal gyrus, temporo-parietal lobe, occipital lobe, striatum, insula and right midbrain. There was no statistical difference in DTI-derived parameters between drug-naive and previously medicated OCD patients. After being medicated, OCD patients showed a reduction in RD of the left striatum and right midbrain, and in MD of the right midbrain. CONCLUSION: Our preliminary findings suggest that abnormalities of white matter microstructure, particularly in terms of myelin integrity, are primarily located within the fronto-striato-thalamo-cortical circuit of individuals with OCD. Some abnormalities may be partly reversed by SSRI treatment.

Symptom severity is more closely associated with social functioning status in inpatients with schizophrenia than cognitive deficits.

BACKGROUND: Prior research has determined that impairment in neurocognition and psychiatric symptoms contribute to reduced occupational and social functioning in schizophrenia. OBJECTIVE: Evaluate the relationships of neurocognition, psychiatric symptoms, and psychosocial functioning in male inpatients with schizophrenia in China. METHODS: Fifty-one male patients currently hospitalised at the Shanghai Mental Health Center with a diagnosis of schizophrenia were recruited and 40 of them were included in the final analysis. Participants were assessed with Chinese versions of the Personal and Social Performance Scale (PSP), Clinical Global Impression-Severity (CGI-S) scale, Positive and Negative Symptom Scale (PANSS), Letter-Number Sequencing Task, and Hong Kong List Learning Test. RESULTS: Robust negative correlations were found between three clinical subscale scores derived from the PANSS and the global measures of social function (the total PSP score and the CGI-S score). Performance on the neurocognitive tasks was not associated with either symptoms or social functioning status. CONCLUSIONS: Among inpatients in the acute phase of schizophrenia, the severity of the clinical symptoms-not the degree of the neurocognitive impairment-is closely associated with the level of social functioning.