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1.
《Bioorganic & medicinal chemistry》2014,22(24):6746-6754
A series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives (7a–q, 10a–q) were designed, synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR, MS and HRMS spectrum. All the compounds were evaluated for the inhibitory activity against mTOR kinase at 10 μM level. Five selected compounds (7b, 7e, 7h, 10b and 10e) were further evaluated for the inhibitory activity against PI3Kα at 10 μM level, and the IC50 values against mTOR kinase and two cancer cell lines. Twelve of the target compounds exhibited moderate antitumor activities. The most promising compound 7e showed strong antitumor activities against mTOR kinase, H460 and PC-3 cell lines with IC50 values of 0.80 ± 0.15 μM, 7.43 ± 1.45 μM and 11.90 ± 0.94 μM, which were 1.28 to 1.71-fold more active than BMCL-200908069-1 (1.37 ± 0.07 μM, 9.52 ± 0.29 μM, 16.27 ± 0.54 μM), respectively. 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 aryl group at C-4 position had a significant impact on the antitumor activities, and 4-OH substitution produced the best potency. 相似文献
2.
Chun-Nan Lin A-Mei Huang Kai-Wei Lin Tzyh-Chyuan Hour Horng-Huey Ko Shyh-Chyun Yang Yeong-Shiau Pu 《Phytochemistry》2010,71(17-18):2140-2146
The diterpenoids (+)-ferruginol (1), ent-kaur-16-en-15-one (2), ent-8(14),15-sandaracopimaradiene-2α,18-diol (3), 8(14),15-sandaracopimaradiene-2α,18,19-triol (4), and (+)-sugiol (5) and the triterpenoids 3β-methoxycycloartan-24(241)-ene (6), 3β,23β-dimethoxycycloartan-24(241)-ene (7), 3β,23β-dimethoxy-5α-lanosta-24(241)-ene (8), and 23(S)-23-methoxy-24-methylenelanosta-8-en-3-one (9), isolated from Amentotaxus formosana, showed inhibitory effects on xanthine oxidase (XO). Of the compounds tested, compound 5 was a potent inhibitor of XO activity, with an IC50 value of 6.8 ± 0.4 μM, while displaying weak ABTS radical cation scavenging activity. Treatment of the bladder cancer cell line, NTUB1, with 3–10 μM of compound 5 and 10 μM cisplatin, and immortalized normal human urothelial cell line, SV-HUC1, with 0.3–1 μM and 10–50 μM of compound 5 and 10 μM cisplatin, respectively, resulted in increased viability of cells compared with cytotoxicity induced by cisplatin. Treatment of NTUB1 with 20 μM cisplatin and 10 or 30 μM of compound 5 resulted in decreased ROS production compared with ROS production induced by cisplatin. These results indicate that 10 or 30 μM of compound 5 in NTUB1 cells may mediate through the suppression of XO activity and reduction of reactive oxygen species (ROS) induced by compound 5 cotreated with 20 μM cisplatin and protection of subsequent cell death. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(10):2324-2328
A series of compounds which contain pyrazole, thiazole and naphthalene ring (1a–7a, 1b–7b, 1c–7c, 1d–7d) were firstly synthesized and their anti-proliferative activity, EGFR inhibitory activity, cytotoxicity and inhibition to Hela cell migration were evaluated. Compound 2-(3-(3,4-dimethylphenyl)-5-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (7d) displayed the most potent inhibitory activity (IC50 = 0.86 μM for Hela and IC50 = 0.12 μM for EGFR). Structure–activity relationship (SAR) analysis showed that the anti-proliferative activity was affected by A-ring-substituent (–OCH3 > –CH3 > –H > –Br > –Cl > –F). Docking simulation of compound 7d into EGFR active site showed that naphthalene ring of 7d with LYS721 formed two p–π bonds, which enhanced antitumor activity. Therefore, compound 7d may be developed as a potential antitumor agent. 相似文献
4.
Yan-Bin Zhang Xiao-Liang Wang Wen Liu Yu-Shun Yang Jian-Feng Tang Hai-Liang Zhu 《Bioorganic & medicinal chemistry》2012,20(21):6356-6365
Three series of novel heterocyclic azoles derivatives containing pyrazine (5a–5k, 8a–8k and 11a–11k) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential telomerase inhibitors. Among the oxadiazole derivatives, compound 5c showed the most potent biological activity against SW1116 cancer cell line (IC50 = 2.46 μM against SW1116 and IC50 = 3.55 μM for telomerase). Compound 8h performed the best in the thiadiazole derivatives (IC50 = 0.78 μM against HEPG2 and IC50 = 1.24 μM for telomerase), which was comparable to the positive control. While compound 11f showed the most potent biological activity (IC50 = 4.12 μM against SW1116 and IC50 = 15.03 μM for telomerase) among the triazole derivatives. Docking simulation by positioning compounds 5c, 8h and 11f into the telomerase structure active site was performed to explore the possible binding model. The results of apoptosis demonstrated that compound 8h possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 8h with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell. Therefore, the introduction of oxadiazole, thiadiazole and triazole structures reinforced the combination of our compounds and the receptor, resulting in progress of bioactivity. 相似文献
5.
《Bioorganic & medicinal chemistry》2016,24(16):3862-3869
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 1.1 μM, 0.92 μM and 8.77–14.3 μM. 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. 相似文献
6.
Yuanchao Xie Bing Huang Kexiang Yu Fangyuan Shi Tianqi Liu Wenfang Xu 《Bioorganic & medicinal chemistry letters》2013,23(12):3556-3560
Recently, many natural products, especially some plant-derived polyphenols have been found to exert antiviral effects against influenza virus and show inhibitory activities on neuraminidases (NAs). In our research, we took caffeic acid which contained two phenolic hydroxyl groups as the basic fragment to build a small compound library with various structures. The enzyme inhibition result indicated that some compounds exhibited moderate activities against NA and compound 15d was the best with IC50 = 7.2 μM and 8.5 μM against N2 and N1 NAs, respectively. The 3,4-dihydroxyphenyl group from caffeic acid was important for the activity according to the docking analysis. Besides, compound 15d was found to be a non-competitive inhibitor with Ki = 11.5 ± 0.25 μM by the kinetic study and also presented anti-influenza virus activity in chicken embryo fibroblast cells. It seemed promising to discover more potent NA inhibitors from caffeic acid derivatives to cope with influenza virus. 相似文献
7.
《Bioorganic & medicinal chemistry》2014,22(7):2366-2378
A novel series of 6-alkenylamides of 4-anilinothieno[2,3-d]pyrimidine derivatives was designed, synthesized and evaluated as irreversible inhibitors of the epidermal growth factor receptor (EGFR). Most of the compounds exhibited good potency against EGFR wild type (EGFR wt) and EGFR T790M/L858R. Among these, the half-maximal inhibitory concentration (IC50) values of 17 compounds against EGFR wt were less than 0.020 μM, and those of 12 compounds were less than 0.010 μM. The IC50 values of 10 compounds against EGFR T790M/L858R were less than 0.005 μM. Compounds 8l, 9n, 9o, 9q and 9v almost completely blocked the phosphorylation of EGFR in the A431 cell line at 1 μM. Compounds 8l, 9n, 9o, 9q and 9v blocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (1 μM), and compound 8l was confirmed to be an irreversible inhibitor through the dilution method. 相似文献
8.
《Bioorganic & medicinal chemistry letters》2014,24(22):5154-5156
A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC50 value of 2.84 μM. Compounds 8k and 8n displayed highly effective antitumor activities against MCF-7 cells, with IC50 values of 4.56 and 4.25 μM, respectively. Compounds 8a and 8n exhibited significant antiproliferative activity against A549 cells, with IC50 values of 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines. 相似文献
9.
Xiaolian Li Qianqian Wang Yang Qing Yanjie Lin Yingli Zhang Xuhong Qian Jingnan Cui 《Bioorganic & medicinal chemistry》2010,18(9):3279-3284
Several 2-(substituted benzo[c,d]indol-2(1H)-ylidene)malononitriles have been designed and synthesized. Their DNA binding, antitumor and DNA damaging properties were evaluated. All the compounds exhibited efficient antitumor activities with preference to be against the tumor cell line 7721 rather than the tumor cell line MCF-7. Compound 1f could intercalate into DNA entirely presumably by the good conjugation of carbonyl group with benzo[c,d]indol moiety. What’s more, 1f exhibited potent toxicity against MCF-7 cells with IC50 at 0.003 μM and against 7721 cells at 0.115 μM, respectively. 相似文献
10.
11.
Jia-Jia Liu Hui Zhang Juan Sun Zhong-Chang Wang Yu-Shun Yang Dong-Dong Li Fei Zhang Hai-Bin Gong Hai-Liang Zhu 《Bioorganic & medicinal chemistry》2012,20(20):6089-6096
A series of novel 4,5-dihydropyrazole derivatives (3a–3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAFV600E) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAFV600E to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAFV600E, MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC50 value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC50 = 1.31 μM for MCF-7 and IC50 = 0.45 μM for WM266.5, IC50 = 0.22 μM for BRAFV600E, 3m: IC50 = 0.97 μM for MCF-7 and IC50 = 0.72 μM for WM266.5, IC50 = 0.46 μM for BRAFV600E, which were comparable with the positive control Erlotinib. 相似文献
12.
Xu Zhang Ting Peng Xun Ji Jian Li Linjiang Tong Zeng Li Wei Yang Yungen Xu Mengyuan Li Jian Ding Hualiang Jiang Hua Xie Hong Liu 《Bioorganic & medicinal chemistry》2013,21(24):7988-7998
A novel series of anilinoquinazoline compounds with C-6 urea-linked side chains was designed and synthesized as reversible inhibitors of epidermal growth factor receptor (EGFR) based on the structure–activity relationships (SARs) of anilinoquinazoline inhibitors. All compounds demonstrated good inhibition of EGFR wild type (EGFR wt) (IC50 = 0.024–1.715 μM) and inhibited proliferation of A431cell line (IC50 = 0.116–22.008 μM). The binding mode of compounds 8a, 8d, 8k and 8o was consistent with the biological results. Moreover, compounds 8k and 8l almost completely blocked the phosphorylation of EGFR in A431 cell line at 0.01 μM. Interestingly, all of the compounds also demonstrated moderate inhibition of EGFR/T790M/L858R (IC50 = 0.049–5.578 μM). In addition, compounds 8f and 8h blocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (10 μM), and compound 8f was confirmed to be an irreversible inhibitor through the dilution method. Importantly, the compounds with C-6 urea-linked side chains which did not contain Michael acceptors demonstrated moderate to strong irreversible EGFR inhibition. 相似文献
13.
Kasiviswanadharaju Pericherla Amir Nasrolahi Shirazi V. Kameshwara Rao Rakesh K. Tiwari Nicholas DaSilva Kellen T. McCaffrey Yousef A. Beni Antonio González-Sarrías Navindra P. Seeram Keykavous Parang Anil Kumar 《Bioorganic & medicinal chemistry letters》2013,23(19):5329-5331
Simple and efficient synthesis of quebecol and a number of its analogs was accomplished in five steps. The synthesized compounds were evaluated for antiproliferative activities against human cervix adenocarcinoma (HeLa), human ovarian carcinoma (SK-OV-3), human colon carcinoma (HT-29), and human breast adenocarcinoma (MCF-7) cancer cell lines. Among all the compounds, 7c, 7d, 7f, and 8f exhibited antiproliferative activities against four tested cell lines with inhibition over 80% at 75 μM after 72 h, whereas, compound 7b and 7g were more selective towards MCF-7 cell line. The IC50 values for compounds 7c, 7d, and 7f were 85.1 μM, 78.7 μM, and 80.6 μM against MCF-7 cell line, respectively, showing slightly higher antiproliferative activtiy than the synthesized and isolated quebecol with an IC50 value of 104.2 μM against MCF-7. 相似文献
14.
《Bioorganic & medicinal chemistry》2016,24(8):1879-1888
On the basis of previous study on 2-methylpyrimidine-4-ylamine derivatives I, further synthetic optimization was done to find potent PDHc-E1 inhibitors with antibacterial activity. Three series of novel pyrimidine derivatives 6, 11 and 14 were designed and synthesized as potential Escherichia coli PDHc-E1 inhibitors by introducing 1,3,4-oxadiazole-thioether, 2,4-disubstituted-1,3-thiazole or 1,2,4-triazol-4-amine-thioether moiety into lead structure I, respectively. Most of 6, 11 and 14 exhibited good inhibitory activity against E. coli PHDc-E1 (IC50 0.97–19.21 μM) and obvious inhibitory activity against cyanobacteria (EC50 0.83–9.86 μM). Their inhibitory activities were much higher than that of lead structure I. 11 showed more potent inhibitory activity against both E. coli PDHc-E1 (IC50 < 6.62 μM) and cyanobacteria (EC50 < 1.63 μM) than that of 6, 14 or lead compound I. The most effective compound 11d with good enzyme-selectivity exhibited most powerful inhibitory potency against E. coli PDHc-E1 (IC50 = 0.97 μM) and cyanobacteria (EC50 = 0.83 μM). The possible interactions of the important residues of PDHc-E1 with title compounds were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that 11d had more potent inhibitory activity than that of 14d or I due to its 1,3,4-oxadiazole moiety with more binding position and stronger interaction with Lsy392 and His106 at active site of E. coli PDHc-E1. 相似文献
15.
Chao-Nan Chen Qiong Chen Yu-Chao Liu Xiao-Lei Zhu Cong-Wei Niu Zhen Xi Guang-Fu Yang 《Bioorganic & medicinal chemistry》2010,18(14):4897-4904
The triazolopyrimidine-2-sulfonanilide, discovered from preparing bioisosteres of the sulfonylurea herbicides, is an important class of acetohydroxyacid synthase (AHAS, EC 4.1.3.18) inhibitors. At least over ten triazolopyrimidine sulfonanilides have been commercialized as herbicides for the control of broadleaf weeds and grass with cereal crop selectivity. Herein, a series of triazolopyrimidine-2-sulfonanilides were designed and synthesized with the aim of discovery of new herbicides with higher activity. The assay results of the inhibition activity of the synthesized compounds against Arabidopsis thatiana AHAS indicated that some compounds showed a little higher activity against flumetsulam (FS), the first commercial triazolopyrimidine-2-sulfonanilide-type herbicide. The ki values of two promising compounds 3d and 8h are respectively, 1.61 and 1.29 μM, while that of FS is 1.85 μM. Computational simulation results indicated the ester group of compound 3d formed hydrogen bonds with the surrounding residues Arg’198 and Ser653, which accounts for its 11.5-folds higher AHAS inhibition activity than Y6610. Further green house assay showed that compound 3d has comparable herbicidal activity as FS. Even at the concentration of 37.5 g.ai/ha, 3d showed excellent herbicidal activity against Galium aparine, Cerastium arvense, Chenopodium album, Amaranthus retroflexus, and Rμmex acetasa, moderate herbicidal activity against Polygonum humifusum, Cyperus iria, and Eclipta prostrate. The combination of in vitro and in vivo assay indicated that 3d could be regarded as a new potential acetohydroxyacid synthase-inhibiting herbicide candidate for further study. 相似文献
16.
《Bioorganic & medicinal chemistry》2014,22(15):4233-4245
Cathepsins have emerged as potential drug targets for melanoma therapy and engrossed attention of researchers for development and evaluation of cysteine cathepsin inhibitors as cancer therapeutics. In this direction, we have designed, synthesized, and assayed in vitro a small library of 30 low molecular weight functionalized analogs of chalcone hydrazones for evaluating structure–activity relationship aspects and inhibitory potency against cathepsin B and H. The maximum inhibitory effect was exerted by chalcone hydrazones, which are open chain analogues followed by their cyclized derivatives, pyrazolines and pyrazoles. All the synthesized compounds were established as reversible inhibitors of these enzymes. Cathepsin B was selectively inhibited by the compounds in each series. Compounds 1d, 2d and 4d were recognized as most potent inhibitors of cathepsin B in this study with Ki values of 0.042 μM, 0.053 μM and 0.131 μM whereas 1b (Ki = 1.111 μM), 2b (Ki = 1.174 μM) and 4b (Ki = 1.562 μM) inhibited cathepsin H activity effectively. And, preeminent cathepsin B inhibitors were –NO2 functionalized however, –Cl substituted moieties were the most persuasive inhibitors for cathepsin H among all the designed compounds. Molecular docking studies performed using iGemdock provided valuable insights. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2014,24(9):2202-2205
Fifteen novel hybrids containing diterpene skeleton and nitric oxide (NO) donor were prepared from isosteviol. All the compounds were tested on preliminary cytotoxicity, and the results showed that six target compounds (8c, 10b, 14a, 14c, 18c, and 18d) exhibited anti-proliferation activity on HepG2 cells, with 8c (IC50 = 4.24 μM) and 18d (IC50 = 2.75 μM) superior to the positive control CDDO-Me (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-acid methyl ester, IC50 = 4.99 μM); eleven target compounds (8a–c, 9a–c, 10a–b, 14a, 14c, 18d) exhibited anti-proliferation activities on B16F10 cells at different levels, among them, seven compounds were more potent than comptothecin (IC50 = 2.78 μM) and CDDO-Me (IC50 = 5.85 μM), particularly, 10b (IC50 = 0.02 μM) presented the strongest effect, which was selected as a candidate for further study. 相似文献
18.
Ho Sik Rho Heung Soo Baek Soo Mi Ahn Jae Won Yoo Duck Hee Kim Han Gon Kim 《Bioorganic & medicinal chemistry letters》2009,19(5):1532-1533
Six diphenolic compounds containing adamantane moiety were synthesized and evaluated as potent inhibitors on tyrosinase activity and melanin formation in melan-a cells. The inhibitory activity of 4-adamantyl resorcinol 1 was similar to that of 4-n-butyl resorcinol in both assays. However, dihydroxyl benzamide derivatives 6a–e showed different inhibitory patterns. All derivatives significantly suppressed the cellular melanin formation without tyrosinase inhibitory activities. These behaviors indicated that the introduction of amide bond changes the binding mode of dihydroxyl groups to tyrosinase. Among derivatives, 6d (3,4-dihydroxyl compound) and 6e (2,3-dihydroxyl compound) showed stronger inhibitory activities (IC50 = 1.25 μM and 0.73 μM, respectively) as compared to 4-n-butyl resorcinol (IC50 = 21.64 μM) and hydroquinone (IC50 = 3.97 μM). This study showed that the position of dihydroxyl substituent at aromatic ring is important for the intercellular inhibition of melanin formation, and also amide linkage and adamantane moiety enhance the inhibition. 相似文献
19.
Mi-hyun Kim Junghun Lee Kyungjin Jung Minjung Kim Yun-Jin Park Heechul Ahn Young Hye Kwon Jung-Mi Hah 《Bioorganic & medicinal chemistry》2013,21(8):2271-2285
1-Heteroaryl-2-aryl-1H-benzimidazole derivatives were synthesized as inhibitors of c-Jun N-terminal kinases, JNK3. Their activities were evaluated through measurement of Kd using SPR, JNK3 kinase assay, and cell-viability of human neuroblastoma cells. Most tested compounds showed high affinity (10 μM–46 nM) to JNK3. Among them, compound 16f exhibited potent activities (Kd = 46 nM). Especially, 16f was also found to present a potent cell protective effect (IC50 = 1.09 μM) against toxicity induced by anisomycin, showing a possibility as protective therapeutics in neuronal cell apoptosis. 相似文献
20.
《Bioorganic & medicinal chemistry》2016,24(21):5374-5379
A novel series of N-arylbenzo[d]oxazol-2-amines (4a–4m) were synthesized and evaluated for their α-glucosidase inhibitory activity. Compounds 4f–4i, 4k and 4m displayed potent inhibitory activity against α-glucosidase with IC50 values in the range of 32.49 ± 0.17–120.24 ± 0.51 μM as compared to the standard drug acarbose. Among all tested compounds, compound 4g having 4-phenoxy substitution at the phenyl ring was found to be the most active inhibitor of α-glucosidase with an IC50 value of 32.49 ± 0.17 μM. Analysis of the kinetics of enzyme inhibition indicated that compound 4g is a noncompetitive inhibitor of α-glucosidase with a Ki value of 31.33 μM. Binding interaction of compound 4g with α-glucosidase was explored by molecular docking simulation. 相似文献