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1.
In silico target fishing approach using PharmMapper server identified c-Met kinase as the selective target for our previously synthesized compound NCI 748494/1. This approach was validated by in vitro kinase assay which showed that NCI 748494/1 possessed promising inhibitory activity against c-Met kinase (IC50 = 31.70 μM). Assessment of ADMET profiling, drug-likeness, drug score as well as docking simulation for the binding pose of that compound in the active site of c-Met kinase domain revealed that NCI 748494/1 could be considered as a promising drug lead. Based on target identification and validation, it was observed that there is structure similarity between NCI 748494/1 and the reported type II c-Met kinase inhibitor BMS-777607. Optimization of our lead NCI 748494/1 furnished newly synthesized 1,2,4-triazine derivatives based on well-established structure-activity relationships, whereas three compounds namely; 4d, 7a and 8c displayed excellent in vitro cytotoxicity against three c-Met addicted cancer cell lines; A549 (lung adenocarcinoma), HT-29 (colon cancer) and MKN-45 (gastric carcinoma); with IC50 values in the range 0.01–1.86 µM. In vitro c-Met kinase assay showed 8c to possess the highest c-Met kinase inhibition profile (IC50 = 4.31 µM). Docking of the active compounds in c-Met kinase active site revealed strong binding interactions comparable to the lead NCI 748494/1 and BMS-777607, suggesting that c-Met inhibition is very likely to be the mechanism of the antitumor effect of these derivatives. 相似文献
2.
Glucosidation of the new 8-amino-6-benzyl(or substituted benzyl)-2,8-dihydro-1,2,4-triazolo[4,3-b][1,2,4]triazin-7(3H)-ones (3a-d) with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide 4 gave the corresponding N-glucosides 5a-d. Chemical transformations leading to new functionalities have also been achieved to give compounds 7-12. Antimicrobial activity of compounds 5a-c against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Escherichia coli is described. 相似文献
3.
Cycloaddition of the reactive intermediates 4 with 1-(cyanomethyl)benzotriazole (5) and its N-2 isomer 9 furnished, after spontaneous rearrangements, the 1,2,4-triazole derivatives 8 and 10. Analogously, reaction of 4 with ethyl cyanoacetate lead to the 1,3,5-trisubstituted 1,2,4-triazoles 12, which gave on treatment with hydrazine the corresponding hydrazides 13. Treatment of 13d with galactose or phenyl isothiocayanate gave the 1-D-galactose-acylhydrazone 14 and the 1,2,4-triazole derivative 15, respectively. Compounds 8c; 10b,c; 13a,c and 14 were selected for the antitumor screening, whereby 8c, 13a, and 13c showed remarkable activity against leukemia, ovarian, renal and lung cancers (8c with Gl(50) of 0.70 microM, 0.07 microM against leukemia (CCRF-CEM and RPMI-8226), 0.02 microM against ovarian (OVCAR-3) and 0.60 microM against renal (CARKI-1) and lung cancers, respectively). 相似文献
4.
The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. Herein we describe the design and synthesis of a novel series of 1,2,4-triazine derivatives based on our lead NCI 748494/1, possessing different N-linkers to aromatic and heterocyclic rings. In addition, a molecular hybrid series combining the 1,2,4-triazine scaffold to the well-known anticancer drug 6-mercaptopurine (6-MP) was synthesized in order to explore its “double-drug” antitumor effect. The synthesized compounds were evaluated for their in vitro antitumor activity against three c-Met addicted cancer cell lines (A549, HT-29 and MKN-45). Most compounds showed moderate to excellent antitumor activity. Compound 3d showed potent inhibitory activity more than reference Foretinib, BMS-777607 and NCI 748494/1 with IC50 values in the range 0.01–0.31 µM against the cancer cell lines. The calculated IC50 of 3d against c-Met kinase was found to be 2.71 µM, which is more potent than NCI 748494/1 (IC50 = 31.70 µM). Docking studies were performed to identify the binding mode of 3d with c-Met kinase domain in comparison to moderate and weak derivatives. The present study clearly demonstrates that 1,2,4-triazine ring exhibits promising antitumor activity and the double-drug optimization strategy led to identifying 3d as a potent c-Met kinase inhibitor suitable for further development. 相似文献
5.
Khalil NS 《Nucleosides, nucleotides & nucleic acids》2005,24(2):111-120
Ribosylation of 3-aryl-5-benzyl(or substituted benzyl)-1,2,4-triazin-6(1H)-/ones or thiones with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose gave the corresponding 3-aryl-5-benzyl(or substituted benzyl)-1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4-triazin-6(1H)-/ones or thiones. The structure of the new ribosides was confirmed chemically and spectroscopically. 相似文献
6.
Selective synthesis and reactions of different 6-substituted-2-beta-D-galactosyl-3-thioxo-2,3-dihydro-1,2,4-triazin-5(4H)-ones using the developed amino or aryl protecting group strategy were investigated. Primary human anticancer screening of twelve selected compounds (in vitro) resulted in an active compound against both MCF7 (Breast) and SF-268(CNS) cell lines. 相似文献
7.
Jaiprakash N. Sangshetti Devanand B. Shinde 《Bioorganic & medicinal chemistry letters》2010,20(2):742-745
An improved protocol for the synthesis of a novel series of 1,2,4-triazines possessing 1,2,3-triazole and piperidine ring using 1-(1-substituted piperidin-4-yl)-1H-1,2,3-triazole-4-carbohydrazide, benzil, ammonium acetate and ZrOCl2·8H2O as a catalyst in ethanol–water has been presented. The yields obtained are in the range of 87–94%. All the synthesized compounds (4a–4l) are novel and were evaluated for their in vitro antifungal activity. SAR for the series has been developed by comparing their MIC values with miconazole and fluconazole. Based on activity data SAR for the series has been developed. Compound 4c from the series was equipotent to miconazole against Candida albicans (MIC-25), Aspergillus niger (MIC-12.5) and Cryptococcus neoformans (MIC-25). Compound 4d was equipotent with miconazole against all tested organisms except Cryptococcus neoformans. Also compound 4i was equipotent with miconazole against C. albicans, A. niger and Fusarium oxysporum. 相似文献
8.
New series of furan–thiazole hybrids (3a-f), thiazolo[2,3-c]-1,2,4-triazines (4a-f), their bioisosteres 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazines (8a-d) and 1,2,4-triazino[4,3-b]-1,2,4-triazines (13a-e) were designed, synthesized and evaluated for their in vitro antitumor activities at the National Cancer Institute (NCI, USA). Among the synthesized compounds, 3d was found to exhibit promising broad spectrum antitumor activity (GI50 MG-MID = 14.22 µM) in a five-dose assay against the full panel NCI-cancer cell lines. 3d displayed higher antitumor activity against most tested cancer cell lines than 5-FU as reference. COMPARE analysis and molecular electrostatic potential computational study revealed that 3d probably exerts its antitumor properties through DNA binding similar to Clomesone. Further DNA binding studies using fluorescent terbium (Tb+3) probe revealed increased fluroresence of DNA-3d-Tb+3 mixture due to damage of the double-stranded DNA. Also, UV–vis absorption study was conducted which showed hyperchromic shift in DNA absorption confirming 3d-induced DNA damage. The assessed potency of 3d-induced DNA damage of calf thymus DNA showed a concentration as low as 2.04 ng/mL for a detectable DNA damage. Moreover, in silico calculation of physicochemical properties and druglikeness were in compliance to Lipinski’s rule. 相似文献
9.
Xue N Yang X Wu R Chen J He Q Yang B Lu X Hu Y 《Bioorganic & medicinal chemistry》2008,16(5):2550-2557
A new series of aryl substituted imidazol-2-one derivatives structurally related to combretastatin A-4 (CA-4) were synthesized and evaluated for their cytotoxic activities in vitro against various human cancer cell lines including MDR cell line. The cytotoxic effects of compounds 7b and 7i proved to be similar to or greater than that of docetaxel. The highly active compound 7b also exhibited excellent inhibitory activity on tumor growth in vivo. 相似文献
10.
《Bioorganic & medicinal chemistry letters》2014,24(7):1685-1691
Twenty six new pyrazoline substituted benzenesulfonylureas (2a–z) were synthesized and tested for in vitro anticancer activity. Fourteen derivatives (2i, 2k–2p, 2r, 2s–2x) were screened for their antiproliferative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Among them four compounds (2i, 2n, 2v and 2x) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM). The compounds 2i, 2n, 2v and 2x showed effective growth inhibition (GI50 MID) values of 2.62, 3.93, 3.33, 3.74 μM respectively beside cytostatic activity TGI (MG-MID) values of 8.42, 65.80, 24.00 and 36.06 μM respectively. The compound 2i displayed remarkable antiproliferative activity in 8 different cell lines with GI50 less than 2 μM. Compounds 2n, 2v and 2x also displayed good antiproliferative activity against 11, 18 and 14 different cell lines respectively with GI50 less than 3 μM. 相似文献
11.
Structure-based drug design was used to systematically synthesize PU3-dimers. The cytotoxicity of PU3 dimers 6 against breast cancer cell lines was evaluated, and their potency increased as the length of the bridging linker increased. Among the compounds tested, 6e with a C-20 linker was the most potent and exhibited a 20- to 30-fold increase in activity compared with that of the parent compound 5. Western blot analyses of the cell lysates treated with 6c revealed that 6c resulted in the concentration-dependent degradation of the Hsp90 client protein Her2, which is consistent with other Hsp90 inhibitors. 相似文献
12.
Khodair AI 《Nucleosides, nucleotides & nucleic acids》2001,20(9):1735-1750
A series of 3-alkyl-5-((Z))-arylidene-2-thiohydantoins 4a-1 were synthesized from the direct condensation of the aromatic aldehydes with 3-alkyl-2-thiohydantoins 3a-c, which in turn were prepared from the reaction of glycine (1) and alkyl isothiocyanates 2a-c. The alkylation of 4a-1 with methylthioethyl chloride gave 5-((Z))-arylidene-3-alkyl-S-(2-methylthioethyl)-2-thiohydantoins 5a-e. S-Glucosylation took place on the reaction of 4a-1 with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide under anhydrous alkaline conditions. These structures have been confirmed from a model study of the coupling of 4a with methylthioethyl chloride and alpha-D-glucose pentaacetate, respectively under Lewis acid conditions. 相似文献
13.
Geminal difluorocyclopropane analogues of nucleosides 7a-7e were synthesized. Compounds 7a and 7c-7e were obtained by alkylation of nucleic acid bases or their appropriate precursors with (cis)-1-benzyloxymethyl-2-bromomethyl-3,3-difluorocyclopropane+ ++ (8). Analogue 7b was prepared by hydrolysis of 2-amino-6-chloropurine derivative 7e. Compounds 7a-7d did not exhibit any antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1 or antitumor effects against murine leukemia L1210, mouse tumors PO3 or C38 and human tumor H15. 相似文献
14.
Glucosidation of the appropriate 1,3 or 1,4-bis(4-amino or arylideneamino-2,4-dihydro-3-thioxo-3H-1,2,4-triazol-5-ylthio)propanes or butanes with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide followed by chromatographic separation gave the corresponding N-, S-, and N,S-bis(glucosides). Chemical transformation leading to new functionalities has been achieved. Antimicrobial screening of 10 selected compounds resulted in their activity against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, and Escherichia coli. 相似文献
15.
Two cyclic tripeptide homologs, cyclo(Glu[Cys-beta-Ala-]-OH) 8a, and cyclo(Glu[Cys-Gaba-]-OH) 8b, were synthesized by the pentafluorophenyl ester method in solution. These cyclic peptides are cyclo homologs of glutathione and are designed as potential antitumor agents. The 1H- and 13C-n.m.r. spectral parameters of cyclo(Glu[Cys(Bzl)-beta-Ala-]-OH) 7a were measured in DMSO-d6 and a possible conformation has been proposed. The cyclic peptide 8a showed low cytotoxic activities against three human tumor cell lines: KB, HeLa, and Colo 205. 相似文献
16.
A convenient strategy is reported for the synthesis of azole nucleoside analogues of D-pinitol (=3-O-methyl-D-chiro-inositol). The key intermediate 3-O-methyl-4,5-epoxy-D-chiro-inositol was obtained in excellent yield via an epoxidation from mono-methanesulfonate of D-pinitol. The process of opening of the epoxy ring by azole-bases appeared strongly regioselective in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. All newly synthesized carbocyclic azole nucleosides were assayed against lung and bladder cancer in vitro. Only the triazole and benzotriazole nucleoside analogues inhibited the growth of human lung cancer cell lines (PG) with EC(50) of 11.3 and 22.6 microM, respectively, and showed much less inhibitory activity against human bladder cell lines (T(24)). 相似文献
17.
Abdel Kader Mansour Yehia A. Ibrahim Nasser S. A. M. Khalil 《Nucleosides, nucleotides & nucleic acids》2013,32(10):2265-2283
Abstract The 6-β-arylvinyl-2- and 4-glucosyl-3-thioxo-2,3-dihydro-1,2,4-triazin-5(4H)-ones were synthesized with high selectivity using the recently developed amino protecting group strategy. The structure of these new glucosides was established chemically and spectroscopically. Also, some interesting chemical transformations and rearrangements were observed. 相似文献
18.
Novel pyrazole and isoxazole derivatives (6-9) were synthesized as a aromatase inhibitors. Pyrazole was synthesized from hydrazine hydrate and isoxazoles from hydroxylamine hydrochloride under different conditions. Molecular docking studies were carried out for the synthesized compounds. The best score was obtained for the compound (9) followed by compound (6) while compound (8) afforded poorest of the score. Aromatase inhibitory activity for compound (6) having pyrazole ring at 2,3 position showed highest activity followed by nitrile derivative (9). Isomeric forms of isoxazole (7 and 8) showed very poor activity compared to fadrozole and aminoglutethimide. Preliminary kinetic studies have shown that both of the active compounds (6 and 9) are reversible inhibitors of the enzyme. 相似文献
19.
Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents
We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI50 values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents. 相似文献
20.
Xin-Hua Liu Hui-Feng Liu Xu Shen Bao-An Song Pinaki S. Bhadury Hai-Liang Zhu Jin-Xing Liu Xing-Bao Qi 《Bioorganic & medicinal chemistry letters》2010,20(14):4163-4167
A series of novel 2-chloro-pyridine derivatives containing flavone, chrome or dihydropyrazole moieties as potential telomerase inhibitors were synthesized. The bioassay tests showed that compounds 6e and 6f exhibited some effect against gastric cancer cell SGC-7901 with IC50 values of 22.28 ± 6.26 and 18.45 ± 2.79 μg/mL, respectively. All title compounds were assayed for telomerase inhibition by a modified TRAP assay, the results showed that compound 6e can strongly inhibit telomerase with IC50 value of 0.8 ± 0.07 μM. Docking simulation was performed to position compound 6e into the active site of telomerase (3DU6) to determine the probable binding model. 相似文献