共查询到20条相似文献,搜索用时 15 毫秒
1.
M. Shahar Yar M. Mustaqeem Abdullah A. Husain M. Afroz Bhakht Erik De Clercq 《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):949-956
3-Chlorobenzofuran-2-carbaldehyde was condensed with substituted acetophenone by using the Claisen-Schmidt condensation to obtain 3-(3-chlorobenzofuran-2-yl)-1-(substituted phenyl)-2-propen-1-one (2a-m) which upon further treatment with hydrazine hydrate gave 2-[3-(substituted phenyl)-4,5-dihydro-1H-5- pyrazolyl)benzofuran-3-yl chloride derivatives (3a-m). All the newly synthesized derivatives were evaluated in vitro for cytotoxicity and antiviral activity in Crandell-Rees Feline Kidney cell, human embryonic lung (HEL) cell, HeLa cell and Vero cell cultures against different viruses. Several compounds, i.e. 2f, 2g, 2i, 2m, 3b, 3d, 3g, 3h and 3m proved quite cytotoxic to the host cells (minimum cytotoxic concentration: 1-10 μg/mL). No specific antiviral activity [50% antivirally effective concentration (EC50) ≥ 5-fold lower than the minimum cytototoxic concentration] was observed for any of the compounds. 相似文献
2.
D'Ambrosio SM Han C Pan L Kinghorn AD Ding H 《Biochemical and biophysical research communications》2011,409(3):465-469
Avocado (Persea americana) fruits are consumed as part of the human diet and extracts have shown growth inhibitory effects in various types of human cancer cells, although the effectiveness of individual components and their underlying mechanism are poorly understood. Using activity-guided fractionation of the flesh of avocado fruits, a chloroform-soluble extract (D003) was identified that exhibited high efficacy towards premalignant and malignant human oral cancer cell lines. From this extract, two aliphatic acetogenins of previously known structure were isolated, compounds 1 [(2S,4S)-2,4-dihydroxyheptadec-16-enyl acetate] and 2 [(2S,4S)-2,4-dihydroxyheptadec-16-ynyl acetate]. In this study, we show for the first time that the growth inhibitory efficacy of this chloroform extract is due to blocking the phosphorylation of EGFR (Tyr1173), c-RAF (Ser338), and ERK1/2 (Thr202/Tyr204) in the EGFR/RAS/RAF/MEK/ERK1/2 cancer pathway. Compounds 1 and 2 both inhibited phosphorylation of c-RAF (Ser338) and ERK1/2 (Thr202/Tyr204). Compound 2, but not compound 1, prevented EGF-induced activation of the EGFR (Tyr1173). When compounds 1 and 2 were combined they synergistically inhibited c-RAF (Ser338) and ERK1/2 (Thr202/Tyr204) phosphorylation, and human oral cancer cell proliferation. The present data suggest that the potential anticancer activity of avocado fruits is due to a combination of specific aliphatic acetogenins that target two key components of the EGFR/RAS/RAF/MEK/ERK1/2 cancer pathway. 相似文献
3.
Ruiming Zou Etsuko Kawashima George A. Freeman George W. Koszalka John C. Drach Leroy B. Townsend 《Nucleosides, nucleotides & nucleic acids》2013,32(1-2):125-153
Abstract Stereoselective glycosylation of 2,5,6-trichlorobenzimidazole (1b), 2-bromo-5,6-dichlorobenzimidazole (1c), 5,6-dichlorobenzimidazole (1d), 5,6-dichlorobenzimidazole-2-thione (1e), 5,6-dichloro-2-(methylthio)benzimidazole (1f), 2-(benzylthio)-5,6-dichlorobenzimidazole (1g), and 2-chloro-5,6-dimethylbenzimidazole (1h) with 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride was achieved to give the desired β nucleosides 2b-h. Subsequent deprotection afforded the corresponding free β-D-2-deoxyribosides 3b-h. The 2-methoxy derivative 3i was synthesized by the treatment of 2b with methanolic sodium methoxide. Displacement of the 2-chloro group of 2b with lithium azide followed by a removal of the protective groups gave the 2-azido-5,6-dichlorobenzimidazole derivative (5). The 2-amino derivative (6) was obtained by hydrogenolysis of 5 over Raney nickel. 5,6-Dichloro-2-isopropylamino-1-(2-deoxy-β-D-erythro-pentofuranosyl)benzimidazole (10) was prepared using 2′-deoxyuridine (7), N-deoxyribofuranosyl transferase and 1d followed by functionalization of the C2 position. Antiviral evaluation of target compounds established that compounds 3b and 3c were active against human cytomegalovirus (HCMV) at non-cytotoxic concentrations. The activity of these 2-deoxy ribosides, however, was less than the activity of the parent riboside, 2,5,6-trichloro-1-β-D-ribofuranosylbenzimidazole (TCRB). Compared to TCRB, 3b and 3c were somewhat more cytotoxic and active against herpes simplex virus type 1. Compounds 3d-i with other substituents in the 2-position were inactive against both viruses and non-cytotoxic. In contrast, compounds with amine substituents in the 2-position (5, 6, 10) were active against HCMV albeit less so than TCRB. These results establish that 2-deoxy-D-ribosyl benzimidazoles are less active against the DNA virus HCMV than are the corresponding D-ribosides. 相似文献
4.
Chronic lithium administration decreases the turnover of arachidonic acid (AA) in several brain phospholipids. This suggests that lithium may attenuate phospholipase A2 (PLA2) activity in brain. We now report effects of chronic lithium treatment on PLA2 activity in postnuclear supernatant from rat brain: Enzyme activity was determined by two assay methods, radiometric and fluorometric, and measured the release of the fatty acid on the second acyl position (sn2) from choline and ethanolamine phospholipids. PLA2 activity in brain postnuclear supernatant from rats chronically treated with lithium in the diet was significantly decreased (20–50%) when compared with controls. In vehicle or lithium-treated rats, PLA2 activity was not significantly augmented or attenuated by the addition of calcium chelators, divalent cations or LiCl supplementation (1.0 mM) to postnuclear supernatant. These results suggest that a major therapeutic effect of lithium is to attenuate brain PLA2 activity involved in signal transduction. 相似文献
5.
Hachemi Kadri Charles S. Matthews Tracey D. Bradshaw Malcolm F. G. Stevens 《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):641-647
A new series of fluorinated and non-fluorinated 2-phenylbenzimidazoles bearing oxygenated substituents on the phenyl ring has been synthesized. Synthesis of the new series was based on our previous discovery of 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (PMX 610) as a potent and selective antitumour agent in vitro (sub-nanomolar GI50 in sensitive human cancer cell lines), but with poor aqueous solubility and lack of a definitive cellular target limiting further development. In this study we test the hypothesis that 2-phenylbenzimidazoles with similar substitution patterns to PMX 610 would retain potent antitumour activity but with potentially superior pharmaceutical properties. In general the new compounds were less active than the former benzothiazole series in vitro when tested against the breast cancer cell lines MCF-7 and MDA 468; however the two most active compounds in the present series (3j and 3k) exhibit low micromolar GI50 values in both cell lines and provide the opportunity for further chemical derivatization with a view to target identification. 相似文献
6.
T. Sudhakar Rao Robert F. Rando John H. Huffman Ganapathi R. Revankar 《Nucleosides, nucleotides & nucleic acids》2013,32(9-10):1997-2008
Abstract In this paper we describe a practical synthesis of 5-nitro-2′-deoxyuridine (4) and 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-nitrouracil (11). These compounds were then evaluated for their ability to inhibit the growth of human cytomegalovirus (HCMV, strain AD169) in MRC-5 cells using a plaque reduction assay. Compound 11 was unable to inhibit the growth of HCMV at the highest concentration tested (100 μg/mL). However, compound 4 (5-NO2-dU) exhibited marginal activity against HCMV in vitro in a dose-dependent manner with a 50% inhibitory concentrations (IC50) of 1 to 5 μg/mL. Combinations of 5-NO2-dU with ganciclovir synergistically inhibited HCMV induced cell killing in culture. 相似文献
7.
8.
Srinivasa Rao Jada Ahmad Sazali Hamzah Nordin Haji Lajis Mohammad Said Saad Malcolm F.G. Stevens Johnson Stanslas 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3)
Andrographolide 1, a diterpenoid lactone of the plant Andrographis paniculata, known to possess antitumour activity in in vitro and in vivo breast cancer models was subjected to semisynthesis leading to the preparation of a number of novel compounds. These compounds exhibited in vitro antitumour activity with moderate to excellent growth inhibition against MCF-7 (breast) and HCT-116 (colon) cancer cells. Compounds 3,19-(2-chlorobenzylidene)andrographolide(5), 3,19-(3-chlorobenzylidene)andrographolide(6), 3,19-(3-fluorobenzylidene)andrographolide(7), 3,19-(4-fluorobenzylidene)andrographolide(8), 3,19-(2-fluorobenzylidene)andrographolide(10), 3,19-(2-chloro-5-nitrobenzylidene)andrographolide (21), 3,19-(4-chlorobenzylidene)andrographolide(30) and 3,19-(2-chloro-4-fluorobenzylidene) andrographolide(31) were also screened against 60 NCI (National Cancer Institute, USA) human tumour cell lines derived from nine cancer cell types. 相似文献
9.
L. W. Hertel C. S. Grossmana J. S. Kroina S. Mineishi S. Chubb B. Nowak 《Nucleosides, nucleotides & nucleic acids》2013,32(5-6):951-955
Abstract 2′,2′-Difluoro analogs of deoxyadenosine (dFdA) and deoxyguanosine (dFdG) were synthesized. The in vitro toxicity and metabolism of dFdA and dFdG was studied in human leukemia cell lines. 相似文献
10.
目的 探讨白质消融性白质脑病中胶质细胞选择性受累而神经元受累轻微的原因。方法 将EIF2B5-RNAi表达载体转染至人星形胶质细胞和人神经元,检测基础状态下及内质网应激(endoplasmic reticulum stress,ERS)后细胞凋亡和活力,检测参与ERS调控的已知和未知miRNA,筛选EIF2B5-RNAi人星形胶质细胞在ERS后miRNA变化。结果 与EIF2B5-RNAi人神经元相比,星形胶质细胞自发凋亡及细胞活力下降。较之神经元,更多miRNA参与星形胶质细胞ERS刺激后的调控,EIF2B5-RNAi组参与调控的miRNA数目显著减少。聚类分析发现,5条已知miRNA是通路连接的关键组分。结论 人星形胶质细胞在ERS后可能更加依赖众多促细胞增殖分化的miRNA修复,而EIF2B5-RNAi人星形胶质细胞存在自发凋亡,ERS后严重减少的miRNA可能导致细胞无法存活。 相似文献
11.
Mostafa M. Ghorab Mansour S. Alsaid Aiten M. Soliman Fatma A. Ragab 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):893-907
Two series of novel 4-(2-(2-(2-(substituted) hydrazinyl)-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 5–17 and 4-(2-(2-(substituted-1H-pyrazol-1-yl)-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 18–24 were synthesised from the starting material 4-(2-(2-hydrazinyl-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 5, to be evaluated for their inhibitory activity towards VEGFR-2. The target compounds 5–24, were screened for their cytotoxic activity against MCF-7 breast cancer cell line and the percentage inhibition against VEGFR-2. Compounds 9, 20, 22 and 23, showed excellent VEGFR-2 inhibitory activity with IC50 ranging from 0.64 to 1.04?µm. Being the most potent, compound 9 was evaluated for its apoptotic inducer effect by studying the effect on caspase-3, it was found to increase its level. Compound 9 boosted the level of Bax and reduced the level of BCl2, compared to the control. Cell cycle analysis was conducted, compound 9 showed cell cycle arrest at G2/M phase. Moreover, mild cytotoxic effect (IC50?=?29.41?µm, respectively) in normal breast cells MCF-12?A, was observed when treated with the same compound. Finally, a molecular docking study was performed to investigate the possible binding interaction inside the active site of the VEGFR-2 enzyme. 相似文献
12.
《Free radical research》2013,47(3):276-292
AbstractAccumulative experimental evidence suggests feasibility of chemotherapeutic intervention targeting human cancer cells by pharmacological modulation of cellular oxidative stress. Current efforts aim at personalization of redox chemotherapy through identification of predictive tumour genotypes and redox biomarkers. Based on earlier research demonstrating that anti-melanoma activity of the pro-oxidant 2,6-dichlorophenolindophenol (DCPIP) is antagonized by cellular NAD(P)H:quinone oxidoreductase (NQO1) expression, this study tested DCPIP as a genotype-directed redox chemotherapeutic targeting homozygous NQO1*2 breast carcinoma, a common missense genotype [rs1800566 polymorphism; NP_000894.1:p.Pro187Ser] encoding a functionally impaired NQO1 protein. In a panel of cultured breast carcinoma cell lines and NQO1-transfectants with differential NQO1 expression levels, homozygous NQO1*2 MDA-MB231 cells were hypersensitive to DCPIP-induced caspase-independent cell death that occurred after early onset of oxidative stress with glutathione depletion and loss of genomic integrity. Array analysis revealed upregulated expression of oxidative (GSTM3, HMOX1, EGR1), heat shock (HSPA6, HSPA1A, CRYAB) and genotoxic stress response (GADD45A, CDKN1A) genes confirmed by immunoblot detection of HO-1, Hsp70, Hsp70B’, p21 and phospho-p53 (Ser15). In a murine xenograft model of human homozygous NQO1*2-breast carcinoma, systemic administration of DCPIP displayed significant anti-tumour activity, suggesting feasibility of redox chemotherapeutic intervention targeting the NQO1*2 genotype. 相似文献
13.
Kamal N. Tiwari John A. Secrist III John A. Montgomery 《Nucleosides, nucleotides & nucleic acids》2013,32(8):1819-1828
Abstract 1,2,3,5-Tetra-O-acetyl-4-thio-D-riboruranose, prepared from 2,3,5-tri-O-benzyl-D-ribofuranose in four steps, was converted to the corresponding 2-chloroadenine nucleoside (8), which was deoxygenated to obtain 2-chloro-2′-deoxy-4′-thioadenosine (12). This is the first report of a 2′-deoxy-4′-thioribonucleoside of a purine rather than a pyrimidine. These novel nucleosides (8 and 12) were cytotoric to several human tumor cell lines in culture. 相似文献
14.
Wagdy M. Eldehna Reem I. Al-Wabli Maha S. Almutairi Adam B. Keeton Gary A. Piazza Hatem A. Abdel-Aziz 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):867-878
In connection with our research program on the development of novel indolin-2-one-based anticancer candidates, herein we report the design and synthesis of different series of hydrazonoindolin-2-ones 3a-e, 5a-e, 7a-c, and 10a-l. The synthesised derivatives were in vitro evaluated for their anti-proliferative activity towards lung A-549, colon HT-29, and breast ZR-75 human cancer cell lines. Compounds 5b, 5c, 7b, and 10e emerged as the most potent derivatives with average IC50 values of 4.37, 2.53, 2.14, and 4.66?µM, respectively, which are superior to Sunitinib (average IC50?=?8.11?µM). Furthermore, compounds 7b and 10e were evaluated for their effects on cell cycle progression and levels of phosphorylated retinoblastoma (Rb) protein in the A-549 cancer cell line. Moreover, 7b and 10e inhibited the cell growth of the multidrug-resistant lung cancer NCI-H69AR cell line with IC50?=?16?µM. In addition, the cytotoxic activities of 7b and 10e were assessed towards three non-tumorigenic cell lines (Intestine IEC-6, Breast MCF-10A, and Fibroblast Swiss-3t3) where both compounds displayed mean tumor selectivity index (1.6 and 1.8) higher than that of Sunitinib (1.4). 相似文献
15.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):545-551
Aminopeptidase N (APN/CD13) over expressed on tumour cells, plays a critical role in tumour invasion, metastasis and tumour angiogenesis. In this article, we described the design, synthesis and preliminary activity studies of novel 3-amino-2-hydroxyl-3-phenylpropanoic acid derivatives as APN inhibitors. The in vitro enzymatic inhibitions on APN from porcine kidney showed that compound 7e had the most potent inhibitory activity against APN with the IC50 value to 1.26?±?0.01 μM, which is better than that of bestatin (IC50?=?2.55?±?0.11 μM). In addition, compound 7e also showed better inhibitory activity against APN on human ovary clear cell carcinoma cell ES-2 than bestatin with the IC50 value to 30.19?±?1.02 μM versus 60.61?±?0.1 μM. Compound 7e could be used as the lead compound in the future for anti-cancer agent research. 相似文献
16.
Gökçe Cihan-Üstündağ Dilek Şatana Gül Özhan Gültaze Çapan 《Journal of enzyme inhibition and medicinal chemistry》2016,31(3):369-380
A new series of indolylhydrazones (6) and indole-based 4-thiazolidinones (7, 8) have been designed, synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. 4-Thiazolidinone derivatives 7g–7j, 8g, 8h and 8j displayed notable antituberculosis (anti-TB) activity showing 99% inhibition at MIC values ranging from 6.25 to 25.0?µg/ml. Compounds 7g, 7h, 7i, 8h and 8j demonstrated anti-TB activity at concentrations 10-fold lower than those cytotoxic for the mammalian cell lines. The indolylhydrazone derivative 6b has also been evaluated for antiproliferative activity against human cancer cell lines at the National Cancer Institute (USA). Compound 6b showed an interesting anticancer profile against different human tumor-derived cell lines at sub-micromolar concentrations with obvious selectivity toward colon cancer cell line COLO 205. 相似文献
17.
Weronika Borek Marta Lewandowska Natalia Kleczewska Piotr Ruszkowski Karol Kacprzak 《Nucleosides, nucleotides & nucleic acids》2013,32(8):507-518
An efficient synthesis of 4-chlorophenyl N-alkyl phosphoramidates of 2?′,3?′-didehydro-2?′,3?′-dideoxyinosine employing 4-chlorophenyl phosphoroditetrazolide as a phosphorylating agent is reported. Improved method for the synthesis of 2?′,3?′-didehydro-2?′,3?′-dideoxyinosine starting from inosine is also described. The synthesized phosphoramidates 11–18 were examined for their cytotoxic activity in three human cancer cell lines: cervical (HeLa), oral (KB), and breast (MCF-7) employing sulforhodamine B assay. The highest activity in all investigated cancer cell lines was displayed by phosphoramidate 13 with N-n-propyl substituent. 相似文献
18.
Sujay Laskar Manuel López-Ortiz Hugo López-Muñoz María L. Escobar-Sánchez Arturo T. Sánchez 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):1129-1135
Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile. 相似文献
19.
F. W. Wang Z. M. Hou C. R. Wang P. Li D. H. Shi 《World journal of microbiology & biotechnology》2008,24(10):2143-2147
The metabolites of endophytic fungus Penicillium sp. from the leaf of Hopea hainanensis were reported for the first time. By bioassay-guided fractionation, the EtOAc extract of a solid-matrix steady culture of
this fungus afforded six compounds, which were identified through a combination of spectral and chemical methods (IR, MS,
1H- and 13C-NMR) to be monomethylsulochrin (1), rhizoctonic acid (2), asperfumoid (3), physcion (4), 7,8-dimethyl-iso-alloxazine (5) and 3,5-dichloro-p-anisic acid (6). Compounds 2, 3 and 6 were obtained from Penicillium sp. for the first time. All of the six isolates were subjected to in vitro bioactive assays including antifungal action against
three human pathogenic fungi Candida albicans, Trichophyton rubrum and Aspergillus niger and cytotoxic activity against the human nasopharyngeal epidermoid tumor KB cell line and human liver cancer HepG2 cell line.
As a result, compounds 2–4 and 6 inhibited the growth of C. albicans with MICs of 40.0, 20.0, 50.0 and 15.0 μg/ml, respectively and the compound 6 showed growth inhibition against A. niger with MICs of 40.0 μg/ml. In addition, compounds 1–3 and 6 exhibited cytotoxic activity against KB cell line with IC50 value of 30.0, 20.0, 20.0, 5.0 μg/ml, respectively and against HepG2 cell line with IC50 value of 30.0, 25.0, 15.0, 10.0 μg/ml, respectively. 相似文献
20.
Igor A. Mikhailopulo Grigorii G. Sivets Tamara I. Pricota Nicolai E. Poopeiko Jan Balzarini Erik De Clercq 《Nucleosides, nucleotides & nucleic acids》2013,32(8):1743-1757
Abstract The oxidation of methyl 5–0-benzyl-3-deoxy-3-fluoro-α-D-arabi-nofuranoside (1) with DMSO/Ac2o afforded a ~ 2:1 mixture of 2-keto derivatives with erythro and threo configuration resulting from isomerization at C3. Successive treatment of the above mixture with MeONH2, LiA1H4, and S-ethyl trifluoroacetate followed by silica gel chromatography afforded methyl 5–0-benzyl-2, 3-dideoxy-3-fluoro-2-(trifluoroacetamido)-α-D-ribofuranoside (6b) and its lyxo isomer 7b in a total yield of 25% and 5%, respectively. The arabino analogue 25 was prepared from 6b. Compounds 6b, 7b and 25 were converted to the corresponding 5–0-benzoyl derivatives 8a, 9 and 26. A series of 2′-amino-2′, 3′-dideoxy-3′-fluoro-β-D-ribo- and-α-D-lyxofuranosides of natural heterocyclic bases have been synthesized starting from 8a and 9. None of the test compounds had any antiviral activity. 3′-Fluoro-2′-amino-2′, 3′-dideoxycytidine (16) was the only compound showing inhibition of murine L1210 and human Molt/4F cell proliferation (50% effective concentration: 39–42μg/m1). 相似文献