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1.
Pyridazinones as selective cyclooxygenase-2 inhibitors   总被引:4,自引:0,他引:4  
Pyridazinone was found to be an excellent core template for selective COX-2 inhibitors. Two potent, selective and orally active COX-2 inhibitors, which were highly efficacious in rat paw edema and rat pyresis models, have been obtained.  相似文献   

2.
Michael adducts of ascorbic acid with alpha,beta-unsaturated carbonyl compounds have been shown to be potent inhibitors of protein phosphatase 1 (PP1) without affecting cell viability at the respective concentrations. Here we were able to show that higher concentrations can partially inhibit PP2A activity and concomitantly induce apoptotic cell death. A nitrostyrene adduct of ascorbic acid proved to be a more potent and effective inhibitor of PP2A as well as a stronger inducer of apoptosis. These adducts only slightly lost their cytotoxic potential in multidrug resistant cells that were 10-fold less sensitive to apoptosis induction by okadaic acid and vinblastine.  相似文献   

3.
Sphingoid bases are growth inhibitory and pro-apoptotic for many types of cells when added to cells exogenously, and can be elevated to toxic amounts endogenously when cells are exposed to inhibitors of ceramide synthase. An important category of naturally occurring inhibitors are the fumonisins, which inhibit ceramide synthase through structural similarities with both the sphingoid base and fatty acyl-CoA co-substrates. Fumonisins cause a wide spectrum of disease (liver and renal toxicity and carcinogenesis, neurotoxicity, induction of pulmonary edema, and others), and most-possibly all-of the pathophysiologic effects of fumonisins are attributable to disruption of the sphingolipid metabolism. The products of alkaline hydrolysis of fumonisins (which occurs during the preparation of masa flour for tortillas) are aminopentols that also inhibit ceramide synthase, but more weakly. Nonetheless, the aminopentols (and other 1-deoxy analogs of sphinganine) are acylated to derivatives that inhibit ceramide synthase, perhaps as product analogs, elevate sphinganine, and kill the cells. Somewhat paradoxically, fumonisins sometimes stimulate growth and inhibit apoptosis, possibly due to elevation of sphinganine 1-phosphate, which is known to have these cellular effects. These findings underscore the complexity of sphingolipid metabolism and the difficulty of identifying the pertinent mediators unless a full profile of the potentially bioactive species is evaluated.  相似文献   

4.
Hydroxymatairesinol (HMR), obtained from the heartwood of spruce (Picea abies), has been demonstrated to exert chemo-preventive effects on the development of mammary tumors in rats. To examine the influence of HMR on uterine carcinogenesis, adult Donryu rats were initiated with a single intrauterine treatment of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at 11 weeks of age and fed thereafter 0, 200, or 600 ppm HMR mixed in the soy-containing diet until 15 months of age. Incidences of uterine adenocarcinoma in both 200 and 600 ppm HMR-dosed groups were significantly reduced to 11% and 15%, respectively, less than 50% of 0 ppm, at the end of the experiment (P < 0.05). A delay in the start of persistent estrus by HMR was observed at 8 months of age compared with controls given carcinogen alone. From urinalysis, HMR was metabolized mainly to enterolactone and hydroxyenterolactone. These findings suggest that HMR or its metabolites exert chemo-preventive effects in the rat ENNG-uterine carcinogenesis model.  相似文献   

5.
A new series of biphenyl methylene indolinones has been designed, synthesized and evaluated for their in vitro antiproliferative activity against various cancer cell lines like DU-145 (prostate cancer cell line), 4T1 (mouse breast cancer cell line), MDA-MB-231 (human breast cancer cell line), BT-549 (human breast cancer cell line), T24 (human urinary bladder carcinoma cell line), and HeLa (cervical cancer cell line). Among the series, compound 10e showed potent in vitro cytotoxic activity against HeLa and DU-145 cancer cell lines with IC50 value of 1.74 ± 0.69 µM and 1.68 ± 1.06 µM respectively. To understand the underlying mechanism of most potent cytotoxic compound 10e, various mechanistic studies were carried out on DU-145 cell lines. Cell cycle analysis results revealed that these conjugates affect both G0/G1 and G2/M phase of the cycle, tubulin binding assay resulted that compound 10e interrupting microtubule network formation by inhibiting tubulin polymerization with IC50 value of 4.96 ± 0.05 μM. Moreover, molecular docking of 10e on colchicine binding site of the tubulin explains the interaction of 10e with tubulin. Clonogenic assay indicated inhibition of colony formation by compound 10e in a dose dependent manner. In addition, morphological changes were clearly observed by AO/EB and DAPI staining studies. Moreover, ROS detection using DCFDA, JC-1, and annexin V-FITC assays demonstrated the significant apoptosis induction by 10e.  相似文献   

6.
Polyphenolic compound chlorogenic acid (CGA) known to be much contained in coffee beans was found to have a regressive effect on induced aberrant crypt foci (ACF) as well as on development of ACF in azoxymethane (AOM)-induced colorectal carcinogenesis in rats. Rice germ and gamma-aminobutyric acid-enriched defatted rice germ inhibited AOM-induced ACF formation and colorectal carcinogenesis in rats. Ferulic acid (FA) also known to be contained in coffee beans and rice prevented AOM-induced ACF formation and intestinal carcinogenesis in rats. Both of food factors, coffee and rice may be of benefit to prevention of human colorectal cancers.  相似文献   

7.
Novel 1,3-diarylcycloalkanopyrazoles 1, and diphenyl hydrazides 2 were identified as selective inhibitors of cyclooxygenase-2. The 1,3-diaryl substitution pattern of the pyrazole ring in 1 differentiates these compounds from most of the known selective COX-2 inhibitors that contain two aryl rings at the adjacent positions on a heterocyclic or a phenyl ring. Similarly, the two phenyl rings in 2 are also separated by three atoms. SAR of both phenyl rings in 1 and 2, and the aliphatic ring in 1 will be discussed.  相似文献   

8.
This paper describes SAR studies involved in the transformation of the NSAID meclofenamic acid into potent and selective cyclooxygenase-2 (COX-2) inhibitors via neutralization of the carboxylate moiety in this nonselective COX inhibitor.  相似文献   

9.
The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.  相似文献   

10.
Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC50 values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15a, 15b, and 15d showed IC50 from 17.39 to 47.10 µM against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15d which came second with regard to antitumor assay with IC50 = 24.10, 40.90, and 33.40 µM against aforementioned cell lines, respectively. Furthermore, Compound 15d increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15d showed IC50 of 253 and 381 nM against HER2 and FGFR, respectively.  相似文献   

11.
Conventional 'nonselective' nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation; however, the potential gastrointestinal risks associated with their use can be a cause for concern. In response to the adverse effects that can accompany nonselective NSAID use, selective cyclo-oxygenase (COX)-2 inhibitors were developed to target the COX-2 isoenzyme, thus providing anti-inflammatory and analgesic benefits while theoretically sparing the gastroprotective activity of the COX-1 isoenzyme. Data from large-scale clinical trials have confirmed that the COX-2 inhibitors are associated with substantial reductions in gastrointestinal risk in the majority of patients who do not receive aspirin. However, some or all of the gastrointestinal benefit of COX-2 inhibitors may be lost in patients who receive low, cardioprotective doses of aspirin, and recent evidence suggests that some of these agents, at some doses, may be associated with an increased risk for cardiovascular adverse events compared with no therapy. The risks and benefits of conventional NSAIDs and of COX-2 inhibitors must be weighed carefully; in clinical practice many patients who might benefit from NSAID or COX-2 therapy are likely to be elderly and at relatively high risk for gastrointestinal and cardiovascular adverse events. These patients are also more likely to be taking low-dose aspirin for cardiovascular prophylaxis and over-the-counter NSAIDs for pain. Identifying therapies that provide relief from arthritis related symptoms, confer optimum cardioprotection, and preserve the gastrointestinal mucosa is complex. Factors to consider include the interference of certain NSAIDs with the antiplatelet effects of aspirin, differences in the adverse gastrointestinal event rates among nonselective NSAIDs and selective COX-2 inhibitors, emerging data regarding the relative risks for cardiovascular events associated with these drugs, and the feasibility and cost of co-therapy with proton pump inhibitors.  相似文献   

12.
Influenza is a respiratory infection that is widespread throughout the world. Its complications are diverse and in many cases include excessive proliferation of cells in the respiratory tract as a factor of the pathogenesis of influenza. The present work studies the effectiveness of using the apoptosis inducer 6-[3-(1-adamantide)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) for prevention of chronic lung lesions at the stage of postinfluenza pneumonia. Mice were infected with influenza virus A/mallard/Pennsylvania/10218/84(H5N2); level of virus reproduction in the lungs, specific lethality to animals, and the morphological structure of foci of postinfluenza pneumonia were then studied at the 15th day post infection. AHPN was shown to decrease the virus’ infectious activity in lung tissue by 1.2–1.5 lgEID50/0.2 mL, depending on the dose used, compared with the control group and to lead to a slight decrease of lethality of animals (the protection index being 12.5–37.5%). Use of AHPN restricted both proliferative and infiltrative components of chronic foci of postinfluenza pneumonia. It exhibited the most pronounced effect on morphology of the lung tissue when used on the fourth to seventh day after infection, i.e., in the period of the greatest activation of processes of the tissue inflammatory infiltration and regeneration of bronchiolar epithelium. Thus, use of apoptosis inducers can prevent development of postinfluenza complications with proliferative component.  相似文献   

13.
In this study, a set of novel benzoxazole derivatives were designed, synthesised, and biologically evaluated as potential VEGFR-2 inhibitors. Five compounds (12d, 12f, 12i, 12l, and 13a) displayed high growth inhibitory activities against HepG2 and MCF-7 cell lines and were further investigated for their VEGFR-2 inhibitory activities. The most potent anti-proliferative member 12 l (IC50 = 10.50 μM and 15.21 μM against HepG2 and MCF-7, respectively) had the most promising VEGFR-2 inhibitory activity (IC50 = 97.38 nM). A further biological evaluation revealed that compound 12l could arrest the HepG2 cell growth mainly at the Pre-G1 and G1 phases. Furthermore, compound 12l could induce apoptosis in HepG2 cells by 35.13%. likely, compound 12l exhibited a significant elevation in caspase-3 level (2.98-fold) and BAX (3.40-fold), and a significant reduction in Bcl-2 level (2.12-fold). Finally, docking studies indicated that 12l exhibited interactions with the key amino acids in a similar way to sorafenib.  相似文献   

14.
Here we investigated the in vivo effect of morin (500 ppm in diet) in fostering apoptosis in diethylnitrosamine (DEN) (200 mg/kg bodyweight) mediated experimental hepatocellular carcinogenesis model. We analyzed the expression of cytosolic protein Akt and their important apoptotic downstream targets like caspase-9, Bcl-2, Bax, GSK-3βin vivo, by immunoblot analysis. In silico docking studies indicated that morin could serve as a better inhibitor than the classical PI3K inhibitor LY294002. The results obtained from in vivo studies confirm this. We also demonstrate here that morin's interaction with a defined set of amino acids of PI3K p110γ catalytic subunit resulted in the down-regulation of p-AktSer473, p-AktThr308 and total Akt causing the attenuation of its downstream targets in DEN-induced hepatocellular carcinoma. Further, morin caused the up-regulation of tumor suppressor PTEN, an important negative regulator of Akt, thus initiating apoptosis. Supplementation of morin to experimental animals modulated Bcl-2/Bax ratio causing the release of cyt C and up-regulation of caspase-3 and -9. Morin was also found to prevent the Akt-mediated suppression of GSK-3β possibly causing cell cycle arrest at the G1/S phase. These observations were supported by the DNA fragmentation and transmission electron microscopy results, which showed the occurrence of apoptosis. In conclusion, our findings demonstrate that morin begets apoptosis in DEN-induced hepatocellular carcinoma.  相似文献   

15.
Overexpression of cyclooxygenase 2 (COX-2) is associated with tumorigenesis in a number of human cancers. Recently, COX-2 overexpression has also been reported in hepatocellular carcinoma (HCC), especially in well-differentiated HCC. However, doubt has been cast on these claims concerning HCC. Here we show by Western blot analysis that COX-2 protein level is higher in the adjacent chronic hepatitis liver than in the tumors themselves. We also show, by immunohistochemical staining, that the mean intensity of COX-2 expression in cirrhotic liver specimens is significantly higher than in normal livers and in moderately-differentiated HCC. In addition, the frequency and level of expression of COX-2 in poorly differentiated HCC was similar to that of well-differentiated HCC. Nevertheless all types of HCC expressed more COX-2 than normal livers, and immunofluorescence staining showed cytoplasmic expression of COX-2 in 7 out of 8 human hepatoma cell lines. Collectively, our data suggest that both chemoprevention and chemotherapy of HCC by COX-2 specific inhibitors should be considered. Our data also suggest that COX-2 may play a role in the advanced stages as well as early stages of hepatocarcinogenesis.  相似文献   

16.
Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is found in grapes and various medical plants. Among cytotoxic, antifungal, antibacterial cardioprotective activity resveratrol also demonstrates non-selective cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition. In order to find more selective COX-2 inhibitors a series of methoxylated and hydroxylated resveratrol derivatives were synthesized and evaluated for their ability to inhibit both enzymes using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE(2) production. Hydroxylated but not methoxylated resveratrol derivatives showed a high rate of inhibition. The most potent resveratrol compounds were 3,3',4',5-tetra-trans-hydroxystilbene (COX-1: IC(50)=4.713, COX-2: IC(50)=0.0113 microM, selectivity index=417.08) and 3,3',4,4',5,5'-hexa-hydroxy-trans-stilbene (COX-1: IC(50)=0.748, COX-2: IC(50)=0.00104 microM, selectivity index=719.23). Their selectivity index was in part higher than celecoxib, a selective COX-2 inhibitor already established on the market (COX-1: IC(50)=19.026, COX-2: IC(50)=0.03482 microM, selectivity index=546.41). Effect of structural parameters on COX-2 inhibition was evaluated by quantitative structure-activity relationship (QSAR) analysis and a high correlation was found with the topological surface area TPSA (r=0.93). Docking studies on both COX-1 and COX-2 protein structures also revealed that hydroxylated but not methoxylated resveratrol analogues are able to bind to the previously identified binding sites of the enzymes. Hydroxylated resveratrol analogues therefore represent a novel class of highly selective COX-2 inhibitors and promising candidates for in vivo studies.  相似文献   

17.
Objectives:  This study aims to identify new anti-cancer agents from Cordyceps -colonizing fungi, using an ecology-based approach. It also aims to explore their anti-cell proliferative mechanisms, and to evaluate their anti-tumour effects in vivo .
Materials and methods:  Extracts from Cordyceps -colonizing fungi were tested on HeLa cells, and active extracts were separated to obtain anti-tumour metabolites; their structures were elucidated by mass and nuclear magnetic resonance spectroscopy. Cell cycle analysis was evaluated using flow cytometry. Tumour formation assays were performed using C57BL/6J mice.
Results:  Based on ecological considerations, the selected extracts were subjected to initial anti-tumour screening. Bioassay-guided fractionation of the active extract afforded two new epipolythiodioxopiperazines, named gliocladicillins A ( 1 ) and B ( 2 ). (A) 1 and B ( 2 ) inhibited growth of HeLa, HepG2 and MCF-7 tumour cells. Further study demonstrated that both preparations arrested the cell cycle at G2/M phase in a dose-dependent manner, and induced apoptosis through up-regulation of expression of p53, p21, and cyclin B, and activation of caspases-8, -9 and -3. These data imply that gliocladicillins A ( 1 ) and B ( 2 ) induce tumour cell apoptosis through both extrinsic and intrinsic pathways. In addition, in vivo studies showed that they displayed significant inhibitory effects on cell population growth of melanoma B16 cells imlanted into immunodeficient mice.
Conclusions:  Gliocladicillins A ( 1 ) and B ( 2 ) are effective anti-tumour agents in vitro and in vivo and should be further evaluated for their potential in clinical use.  相似文献   

18.
As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure-activity relationships of this class of molecules were explored. Compound 1k, with EC(50) of 270 nM and GI(50) of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid.  相似文献   

19.
A series of novel sulfone substituted 4,5-diarylthiazoles have been synthesized and evaluated for their inhibition of the two isoforms of human cyclooxygenase (COX-1 and COX-2). This series displays exceptionally selective COX-2 inhibition.  相似文献   

20.
A series of terphenyl based 4-aza-2,3-didehydropodophyllotoxin conjugates (8ar) were synthesized by a straightforward one-step multicomponent synthesis that demonstrated anticancer activity against five human cancer cell lines (lung, colon, renal, prostate and cervical). All the tested compounds showed potent anticancer activity with IC50 values ranging from 0.87 to 16.59 μM. Among them compounds 8n and 8p showed significant anticancer activity in lung cancer cells with IC50 values 0.91 and 0.87 μM, respectively. Flow cytometric analysis revealed that these compounds induced cell cycle arrest in G2/M phase in A549 cell line leading to caspase-3 dependent apoptotic cell death. The tubulin polymerization assay and immunofluorescence analysis showed that these compounds effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Further, Hoechst staining, DNA fragmentation analysis also suggested that these compounds induced cell death by apoptosis. Overall, the current study demonstrated that the synthesis of terphenyl based 4-aza-2,3-didehydropodophyllotoxin conjugates as promising anticancer agents with G2/M cell cycle arrest and apoptotic-inducing activities via targeting tubulin.  相似文献   

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