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1.
J Biol Chem ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005668

RESUMO

Cytotoxic molecules can kill cancer cells by disrupting critical cellular processes or by inducing novel activities. 6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, is a small molecule that kills cancer cells by generation of novel activity.  DNMDP induces complex formation between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) and specifically kills cancer cells expressing elevated levels of these two proteins.  Here, we examined the characteristics and covariates of the cancer cell response to DNMDP.  On average, the sensitivity of human cancer cell lines to DNMDP is correlated with PDE3A expression levels.  However, DNMDP could also bind the related protein, PDE3B, and PDE3B supported DNMDP sensitivity in the absence of PDE3A expression.  Although inhibition of PDE3A catalytic activity did not account for DNMDP sensitivity, we found that expression of the catalytic domain of PDE3A in cancer cells lacking PDE3A is sufficient to confer sensitivity to DNMDP, and substitutions in the PDE3A active site abolish compound binding.  Moreover, a genome-wide CRISPR screen identified the aryl hydrocarbon receptor interacting protein (AIP), a co-chaperone protein, as required for response to DNMDP.  We determined that AIP is also required for PDE3A-SLFN12 complex formation.  Our results provide mechanistic insights into how DNMDP induces PDE3A-SLFN12 complex formation, thereby killing cancer cells with high levels of PDE3A and SLFN12 expression.

2.
PLoS One ; 15(2): e0228493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027673

RESUMO

Domestic yak (Bos grunniens) is the most crucial livestock in the Qinghai-Tibetan Plateau, providing meat and other necessities for local people. The skeletal muscle of adult livestock is composed of muscle fibers, and fiber composition in muscle has influence on meat qualities, such as tenderness, pH, and color. Real-time quantitative polymerase chain reaction (RT-qPCR) is a powerful tool to evaluate the gene expression of muscle fiber, but the normalization of the data depends on the stability of expressed reference genes. Unfortunately, there is no consensus for an ideal reference gene for data normalization in muscle tissues of yak. In this study, we aimed to assess the stability of 14 commonly used candidate reference genes by using five algorithms (GeNorm, NormFinder, BestKeeper, Delat Ct and Refinder). Our results suggested UXT and PRL13A were the most stable reference genes, while the most commonly used reference gene, GAPDH, was most variably expressed across different muscle tissues. We also found that the extensor digitorum lateralis (EDL), trapezius pars thoracica (TPT), and psoas major (PM) muscle had the higher content of type I muscle fibers and the lowest content of type IIB muscle fibers, while gluteobiceps (GB) muscle had the highest content of type IIB muscle fibers. Our study provides the suitable reference genes for accurate analysis of yak muscle fiber composition.

3.
J Virol ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969439

RESUMO

P3N-PIPO, the only dedicated movement protein (MP) of potyviruses, directs cylindrical inclusion (CI) protein from the cytoplasm to the plasmodesma (PD), where CI forms conical structures for intercellular movement. To better understand potyviral cell-to-cell movement, we further characterized P3N-PIPO using Turnip mosaic virus (TuMV) as a model virus. We found that P3N-PIPO interacts with P3 via the shared P3N domain and that TuMV mutants lacking the P3N domain of either P3N-PIPO or P3 are defective in cell-to-cell movement. Moreover, we found that the PIPO domain of P3N-PIPO is sufficient to direct CI to the PD, whereas the P3N domain is necessary for localization of P3N-PIPO to 6K2-labeled vesicles or aggregates. Finally, we discovered that the interaction between P3 and P3N-PIPO is essential for the recruitment of CI to cytoplasmic 6K2-containing structures and the association of 6K2-containing structures with PD-located CI inclusions. These data suggest that both P3N and PIPO domains are indispensable for potyviral cell-to-cell movement and that the 6K2 vesicles in proximity to PDs resulting from multipartite interactions among 6K2, P3, P3N-PIPO and CI may also play an essential role in this process.Author Summary Potyviruses include numerous economically important viruses that represent approximately 30% of known plant viruses. However, there is still limited information about the mechanism of potyviral cell-to-cell movement. In the present study, we show that P3N-PIPO interacts with and recruits CI to the PD via the PIPO domain, and interacts with P3 via the shared P3N domain. We further report that the P3N-PIPO and P3 interaction is associated with 6K2 vesicles and brings the 6K2 vesicles into proximity with PD-located CI structures. These results support the notion that the replication and cell-to-cell movement of potyviruses are coupled processes by anchoring viral replication complexes at the entrance of PDs, which greatly increase our knowledge of the intercellular movement of potyviruses.

4.
Arch Virol ; 165(1): 257-260, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31773325

RESUMO

A new geminivirus was identified in common bean (Phaseolus vulgaris) showing severe stunt and leaf curling symptoms in Heilongjiang province of China, via sequencing and assembly of small RNAs. The genome of this geminivirus comprises 2,959 nucleotides (nt) and shares 21.77-54.97% nt sequence identity with other geminiviruses. The coat protein (CP) shares the highest amino acid (aa) sequence identity (23.5%) with that of sesame curly top virus (SeYMV; genus Turncurtovirus), whereas the C1 (Rep) shares the highest aa sequence identity (66.5%) with that of beet severe curly top virus (BSCTV; genus Curtovirus). This geminivirus neighbors the turncurtoviruses in phylogenetic trees based on the full genome sequence or the amino acid sequence of the Rep protein, but it forms a distinct clade in the phylogenetic tree based on the coat protein. Recombination analysis showed that parts of the C1 coding region of this geminivirus were recombined from a curtovirus or turncurtovirus. Based on these results, the name "common bean curly stunt virus" (CBCSV) is proposed for this virus.


Assuntos
Geminiviridae/genética , Phaseolus/virologia , Vírus Reordenados/genética , Sequência de Aminoácidos , Proteínas do Capsídeo/genética , China , Evolução Molecular , Geminiviridae/classificação , Tamanho do Genoma , Filogenia , Folhas de Planta/virologia , Vírus Reordenados/classificação , Sequenciamento Completo do Genoma
5.
Eur J Med Chem ; 187: 111966, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31869655

RESUMO

A new class of 2-amino-4-(1,2,4-triazol)pyridine derivatives were designed and synthesized as potent epidermal growth factor receptor inhibitors. In particular, compound 10c exhibited significant inhibitory against EGFRL858R/T790M, and also displayed potent anti-proliferative activity against non-small cell lung cancer cell line H1975. Besides, compound 10j showed potent inhibitory activity against glioblastoma cell line U87-EGFRvⅢ, which was at least 3-fold more potent than Osimertinib and 25-fold superior to Lazertinib. Moreover, molecular modeling and molecular dynamics simulations disclosed the binding model of the most active compound to the domain of EGFR. This contribution provides 2-amino-4-(1,2,4-triazol)pyridines as a new scaffold for EGFRT790M and/or EGFRvⅢ inhibitor.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31802556

RESUMO

Since China initiated new health-care reforms in early 2009, a variety of measures have been implemented to slow the growth of medical expenses. This study was conducted to investigate the effect of controlling medical expenses. Based on inpatients' medical expenses at the largest tertiary hospital in Shenzhen, China, from 2009 to 2017, this study analyzed the changes in medical expenses and expense structures according to payment sources (insured or self-financed), stratifying the medical expenses according to the ICD-10 classification chapters of the principal diagnoses of the inpatients in two years (2009 and 2017) in order to control for confounding diseases. The results showed that mean inpatient expenses continued to rise from 2009 to 2017, and the expenses of the self-financed group began to exceed those of the insured group after 2011. Drug and consumable expenses were still the main factors that affected inpatient expenses, and consumable expenses remarkably increased, becoming the highest proportion of expenses. New health-care reforms were effective in controlling growing medical expenses for insured patients but did not make a significant difference in the expenses of self-financed patients. The excessive use of consumables has become a new driver of growing medical expenses.

7.
J Biomol Struct Dyn ; : 1-7, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31870220

RESUMO

Tropomyosin receptor kinase A (Trk A) is a receptor tyrosine kinase activated by nerve growth factor (NGF). TrkA plays an important role in pain sensation, which leads to significant interest in the development of small molecule inhibitors of TrkA. However, TrkA and the other two highly homologous isoforms, TrkB and TrkC, are highly conserved in the ATP binding site, which suggests that achieving TrkA subtype selectivity over TrkB and TrkC in this site may be extremely challenging. Allosteric inhibitors without making any interactions with the conserved ATP binding site may present a more promising approach. Recently, selective TrkA inhibitors 1 and 2 were reported to be allosteric inhibitors targeting the DFG-out allosteric pocket. In the present study, molecular dynamics simulations and free energy calculations were carried out on TrkA in complex with ligands 1 and 2, which was expected to provide a basis for the rational drug design of TrkA allosteric inhibitors.

8.
Genes (Basel) ; 10(12)2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31779203

RESUMO

DNA methylation modifications are implicated in many biological processes. As the most common epigenetic mechanism DNA methylation also affects muscle growth and development. The majority of previous studies have focused on different varieties of yak, but little is known about the epigenetic regulation mechanisms in different age groups of animals. The development of muscles in the different stages of yak growth remains unclear. In this study, we selected the longissimus dorsi muscle tissue at three different growth stages of the yak, namely, 90-day-old fetuses (group E), six months old (group M), and three years old (group A). Using RNA-Seq transcriptome sequencing and methyl-RAD whole-genome methylation sequencing technology, changes in gene expression levels and DNA methylation status throughout the genome were investigated during the stages of yak development. Each group was represented by three biological replicates. The intersections of expression patterns of 7694 differentially expressed genes (DEGs) were identified (padj < 0.01, |log2FC| > 1.2) at each of the three developmental periods. Time-series expression profile clustering analysis indicated that the DEGs were significantly arranged into eight clusters which could be divided into two classes (padj < 0.05), class I profiles that were downregulated and class II profiles that were upregulated. Based on this cluster analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that DEGs from class I profiles were significantly (padj < 0.05) enriched in 21 pathways, the most enriched pathway being the Axon guidance signaling pathway. DEGs from the class II profile were significantly enriched in 58 pathways, the pathway most strongly enriched being Metabolic pathway. After establishing the methylation profiles of the whole genomes, and using two groups of comparisons, the three combinations of groups (M-vs.-E, M-vs.-A, A-vs.-E) were found to have 1344, 822, and 420 genes, respectively, that were differentially methylated at CCGG sites and 2282, 3056, and 537 genes, respectively, at CCWGG sites. The two sets of data were integrated and the negative correlations between DEGs and differentially methylated promoters (DMPs) analyzed, which confirmed that TMEM8C, IGF2, CACNA1S and MUSTN1 were methylated in the promoter region and that expression of the modified genes was negatively correlated. Interestingly, these four genes, from what was mentioned above, perform vital roles in yak muscle growth and represent a reference for future genomic and epigenomic studies in muscle development, in addition to enabling marker-assisted selection of growth traits.

9.
ACS Med Chem Lett ; 10(11): 1537-1542, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31749907

RESUMO

6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, potently and selectively inhibits phosphodiesterases 3A and 3B (PDE3A and PDE3B) and kills cancer cells by inducing PDE3A/B interactions with SFLN12. The structure-activity relationship (SAR) of DNMDP analogs was evaluated using a phenotypic viability assay, resulting in several compounds with suitable pharmacokinetic properties for in vivo analysis. One of these compounds, BRD9500, was active in an SK-MEL-3 xenograft model of cancer.

10.
Front Pediatr ; 7: 421, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681718

RESUMO

Background: Doppler echocardiography (D-ECHO) is a commonly used imaging tool for both diagnosis and follow-up examination of congenital heart disease (CHD). The goal of this study is to evaluate the accuracy of D-ECHO as used to measure an estimate sPAP in pediatric patients with CHD. Methods: A prospective study in 397 pediatric patients with CHD has been carried out to compare estimate sPAP measured with D-ECHO to that measured with right heart catheterization (RHC). Pearson correlation analyses were used to calculate the correlation coefficients between RHC and D-ECHO. Bland-Altman analyses were carried out to assess the agreement between the two methods. Results: Our data have demonstrated a significant underestimation of sPAP by D-ECHO compared to that by RHC. A strong correlation (r = 0.957, p < 0.01) was found between sPAP (36.1 ± 14.9 mmHg) and RVSP (36.0 ± 14.5 mmHg) measured with RHC. However, a relatively weak correlation (r = 0.219, p < 0.01) was observed between sPAP (36.1 ± 14.9 mmHg) measured during RHC and sPAP (28.7 ± 9.7 mmHg) as estimated using D-ECHO. The Bland-Altman analysis demonstrated that the bias for D-ECHO sPAP estimates was 6.6 mmHg with 95% limits of agreement ranging from -23.6 to 36.8 mmHg. A total of 57.5% of D-ECHO measurements were found to be accurate, with accuracy predefined as 95% of agreement within ±10 mmHg for sPAP estimates. Conclusions: sPAP measured with D-ECHO may be underestimated in pediatric patients with CHD.

11.
Genes (Basel) ; 10(11)2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31671664

RESUMO

Testis-specific genes play an essential part in the centromere union during meiosis in male germ cells, spermatogenesis, and in fertility. Previously, there was no research report available on the expression pattern of SYCP3 and TSEG2 genes in different ages of yaks. Therefore, the current research compared the expression profiling of SYCP3 and TSEG2 genes in testes of yaks. The expression pattern of SYCP3 and TSEG2 mRNA was investigated using qPCR, semi-quantitative PCR, western blot, immunohistochemistry, and molecular bioinformatics. Our findings displayed that SYCP3 and TSEG2 genes were prominently expressed in the testicles of yaks as compared to other organs. On the other hand, the protein encoded by yak SYCP3 contains Cor1/Xlr/Xmr conserved regions, while the protein encoded by yak TSEG2 contains synaptonemal complex central element protein 3. Additionally, multiple alignments sequences indicated that proteins encoded by Datong yak SYCP3 and TSEG2 were highly conserved among mammals. Moreover, western blot analysis specified that the molecular mass of SYCP3 protein was 34-kDa and TSEG2 protein 90-kDa in the yak. Furthermore, the results of immunohistochemistry also revealed the prominent expression of these proteins in the testis of mature yaks, which indicated that SYCP3 and TSEG2 might be essential for spermatogenesis, induction of central element assembly, and homologous recombination.

12.
Animals (Basel) ; 9(11)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703249

RESUMO

The aim of this study was to explore the possibility of applying GP to important economic traits in the domesticated yak, thus providing theoretical support for its molecular breeding. A reference population was constructed consisting of 354 polled yaks, measuring four growth traits and eight hematological traits related to resistance to disease (involved in immune response and phagocytosis). The Illumina bovine HD 770k chip was used to obtain SNP information of all the individuals. With these genotypes and phenotypes, GBLUP, Bayes B and Bayes Cπ methods were used to predict genomic estimated breeding values (GEBV) and assess prediction capability. The correlation coefficient of the association of GEBV with estimated breeding value (EBV) was used as PA for each trait. The prediction accuracy varied from 0.043 to 0.281 for different traits. Each trait displayed similar PAs when using the three methods. Lymphocyte counts (LYM) exhibited the highest predictive accuracy (0.319) during all GP, while chest girth (CG) provided the lowest predictive accuracy (0.043). Our results showed moderate PA in most traits such as body length (0.212) and hematocrit (0.23). Those traits with lower PA could be improved by using SNP chips designed specifically for yak, a better optimized reference group structure, and more efficient statistical algorithms and tools.

13.
Animals (Basel) ; 9(11)2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31717620

RESUMO

Investigating the critical genes related to milk synthesis is essential for the improvement of the milk yield of the yak. Real-time quantitative polymerase chain reaction (RT-qPCR) is a reliable and widely used method to measure and evaluate gene expression levels. Selection of suitable reference genes is mandatory to acquire accurate normalization of gene expression results from RT-qPCR. To select the most stable reference genes for reliable normalization of mRNA expression by RT-qPCR in the mammary gland of the Ashidan yak, we selected 16 candidate reference genes and analyzed their expression stability at different physiological stages (lactation and dry period). The expression stability of the candidate reference genes was assessed using geNorm, NormFinder, BestKeeper, Delta Ct, and RefFinder methods. The results showed that the hydroxymethylbilane synthase gene (HMBS) and the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide gene (YWHAZ) were the most stable genes across all treatment samples. The reliability of selected reference genes was validated by normalizing relative expression of the lactation-related 60S ribosomal protein L35 gene (RPL35). The relative expression of RPL35 varied considerably according to the different reference genes. This work provides valuable information to further promote research in the molecular mechanisms involved in lactation and mammary gland development and provides a foundation for the improvement of the milk yield and quality of the Ashidan yak.

14.
Biomed Res Int ; 2019: 5198138, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737667

RESUMO

Artemisitene (ATT) activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) by increasing its stabilization and reducing ubiquitination. The cysteine (Cys) residues of the cytosolic Nrf2 repressor Kelch-like ECH-associated protein-1 (Keap1) function as redox sensors and may be crucial in activating Nrf2. To determine whether ATT-induced Nrf2 activation is dependent on the modification of Keap1 and to elucidate the underlying mechanism, we transfected cell lines with six different Keap1 mutant constructs, each with a Cys (-77, -151, -257, -273, -288, and -297) to Ser substitution. Only the Cys151Ser mutant prevented ATT-mediated activation of Nrf2, indicating that the Cys151 residue of Keap1 likely interacts with ATT and is essential for Nrf2 stabilization and transcription of downstream genes. Our finding provides a pharmacological basis for using artemisitene against oxidative stress-related diseases.

15.
Acta Pharmacol Sin ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729469

RESUMO

Dengue fever is an acute infectious disease caused by dengue virus (DENV) and transmitted by Aedes mosquitoes. There is no effective vaccine or antiviral drug available to date to prevent or treat dengue disease. Recently, RNA-dependent RNA polymerase (RdRp), a class of polymerases involved in the synthesis of complementary RNA strands using single-stranded RNA, has been proposed as a promising drug target. Hence, we screened new molecules against DENV RdRp using our previously constructed virtual screening method. Mol-5, [1,2,4]triazolo[1,5-a]pyrimidine derivative, was screened out from an antiviral compound library (~8000 molecules). Using biophysical methods, we confirmed the direct interactions between mol-5 and purified DENV RdRp protein. In luciferase assay, mol-5 inhibited NS5-RdRp activity with an IC50 value of 1.28 ± 0.2 µM. In the cell-based cytopathic effect (CPE) assay, mol-5 inhibited DENV2 infectivity with an EC50 value of 4.5 ± 0.08 µM. Mol-5 also potently inhibited DENV2 RNA replication as observed in immunofluorescence assay and qRT-PCR. Both the viral structural (E) and non-structural (NS1) proteins of DENV2 were dose-dependently decreased by treatment with mol-5 (2.5-10 µM). Mol-5 treatment suppressed DENV2-induced inflammation in host cells, but had no direct effect on host defense (JAK/STAT-signaling pathway). These results demonstrate that mol-5 could be a novel RdRp inhibitor amenable for further research and development.

16.
Sleep Med ; 63: 82-87, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31606653

RESUMO

OBJECTIVE: To evaluate the effect of insomnia after acute ischemic stroke on cerebrovascular reactivity (CVR). METHODS: A total of 158 eligible patients with acute ischemic stroke were enrolled prospectively. Of these, six patients were lost to follow-up, and 152 were included in the final analysis. The patients were divided into the insomnia (N = 24) and non-insomnia (N = 128) groups based on the Athens Insomnia Scale. The insomnia group was further divided into benzodiazepine (BDZ) and non-BDZ treatment groups according to BDZ use status after ischemic stroke. The transcranial doppler ultrasound (TCD) breath-holding test was performed to calculate the breath-holding index (BHI) of the responsible cerebral middle artery, which was used to evaluate CVR. Then, univariate and multivariate linear regression analyses were carried out to determine the effect of insomnia after acute ischemic stroke on CVR. RESULTS: At one month after the onset of acute ischemic stroke, TCD-BHI was significantly higher in the non-insomnia group compared with the insomnia group (p = 0.027). In patients with insomnia, TCD-BHI was significantly higher in the BDZ treatment group compared with non-BDZ treatment group (p = 0.039). With age, hypertension, diabetes, hyperlipidemia, long-term smoking, blood homocysteine, and Athens Insomnia Scale score as independent variables, and TCD-BHI at one month after onset as a dependent variable, univariate and multivariate linear regression analyses indicated that the Athens Insomnia Scale score was an independent factor affecting TCD-BHI (regression coefficient, -0.013; 95% confidence interval (CI) -0.024 to -0.003). CONCLUSION: Insomnia after acute ischemic stroke is an independent risk factor for CVR.

17.
Arch Med Sci ; 15(5): 1154-1162, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31572460

RESUMO

Introduction: Endothelin receptor type B (EDNRB) is a potential target gene of miR-124-3p, but the association between miR-124-3p and EDNRB has not yet been reported. The aim of this study was to investigate the role of miR-124-3p in bladder cancer (BC) and to determine whether miR-124-3p regulates cell proliferation by targeting EDNRB. Material and methods: Bladder cancer tissues and cell lines were obtained in order to analyze the miR-124-3p and EDNRB expression through quantitative RT-PCR (qRT-PCR) and western blotting analysis. The dual-luciferase reporter assay was employed to confirm the relationship between miR-124-3p and EDNRB. The manipulation of miR-124-3p and EDNRB expression was achieved through cell transfection. Cell proliferation and apoptosis were evaluated by MTS assay, colony forming assay and flow cytometry. A nude mouse tumorigenicity assay was used to detect the effects of miR-124-3p in vivo. Results: There was an inverse correlation between the expression of miR-124-3p and EDNRB; miR-124-3p was down-regulated and EDNRB was up-regulated in BC tissues and cell lines. MiR-124-3p was observed to target EDNRB and suppress its expression. Other studies have suggested that the transfection of miR-124-3p mimics and EDNRB siRNA can suppress BC cell proliferation and induce cell apoptosis. Conclusions: miR-124-3p regulates the proliferation and apoptosis of BC cells by suppressing EDNRB expression.

18.
Bioorg Med Chem ; 27(16): 3729-3734, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31278004

RESUMO

As a known natural product with anti-tumor activity, honokiol has been widely researched and structural modified. Lots of honokiol derivatives have been found to possess good anti-proliferative activity and showed great potential in cancer therapy, but the SAR (structure-activity relationship) was still confused. Here in, the SAR were comprehensively researched by summary of reported derivatives and synthesis of novel derivatives. Amongst novel derivatives, the promising compounds A6 and A10 exhibited potent and selective anti-proliferative activities against K562 cell line with the IC50 values of 5.04 and 7.08 µM respectively. The SAR was discussed around honokiol and 79 derivatives by the means of CoMFA and theoretical calculation, which provided useful suggestion for further structural optimization of honokiol derivatives.

19.
Eur J Med Chem ; 179: 358-375, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260890

RESUMO

ALK and ROS1 kinases have become promising therapeutic targets since Crizotinib was used to treat non-small-cell lung cancer clinically. Aiming to explore new potent inhibitors, a series of 2-amino-4-(1-piperidine) pyridine derivatives that stabilized a novel DFG-shifted conformation in the kinase domain of ALK were designed and synthesized on the base of lead compound A. Biological evaluation highlighted that most of these new compounds could also potently inhibit ROS1 kinase, leading to the promising inhibitors against both ROS1 and ALK. Among them, the representative compound 2e stood out potent anti-proliferative activity against ALK-addicted H3122 and ROS1-addicted HCC78 cell lines (IC50 = 6.27 µM and 10.71 µM, respectively), which were comparable to that of Crizotinib. Moreover, 2e showed impressive enzyme activity against clinically Crizotinib-resistant ALKL1196M with an IC50 value of 41.3 nM, which was about 2-fold more potent than that of Crizotinib. 2e also showed potent inhibitory activity in about 6-fold superior to Crizotinib (IC50: 104.7 nM vs. 643.5 nM) in Ba/F3 cell line harboring ROS1G2032R. Furthermore, molecular modeling disclosed that all the representative inhibitors could dock into the active site of ALK and ROS1, which gave a probable explanation of anti Crizotinib-resistant mutants. These results indicated that our work has established a path forward for the generation of anti Crizotinib-resistant ALK/ROS1 dual inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Células A549 , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Piridinas/química , Relação Estrutura-Atividade
20.
Org Lett ; 21(12): 4859-4863, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31192614

RESUMO

A Pd-catalyzed formal [5 + 3] intermolecular cycloaddition reaction of isatin-derived α-(trifluoromethyl)imines with aryl substituted vinylethylene carbonates (VECs) has been reported, affording trifluoromethyl-group-containing spirooxindoles fused with an eight-membered ring as a single diastereoisomer in good yields in the presence of a Brønsted acid in a one-pot manner under mild conditions. The asymmetric version of this reaction has been also realized using a chiral phosphine ligand along with the further transformation of the obtained product to give a spirooxindolo pyrrolidine derivative upon oxidation.

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