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1.
A series of novel (E)-3-(3,4-dihydroxyphenyl)acrylylpiperazine derivatives had been synthesized and evaluated their biological activities as potential tubulin polymerization inhibitors. Among these compounds, compound 3q exhibited potent antiproliferative activities against three cancer cell lines in vitro, and antitubulin polymerization activity with IC50 of 0.92 μM, which was superior to that of colchicine (IC50 = 1.34 μM). Docking simulation was performed to insert compound 3q into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. These results suggested that compound 3q may be a promising antitubulin agent for the potential treatment of cancer.  相似文献   

2.
Based on our prior antitumor hits, 32 novel N-alkyl-N-substituted phenylpyridin-2-amine derivatives were designed, synthesized and evaluated for cytotoxic activity against A549, KB, KBVIN, and DU145 human tumor cell lines (HTCL). Subsequently, three new leads (6a, 7g, and 8c) with submicromolar GI50 values of 0.19–0.41 μM in the cellular assays were discovered, and these compounds also significantly inhibited tubulin assembly (IC50 1.4–1.7 μM) and competitively inhibited colchicine binding to tubulin with effects similar to those of the clinical candidate CA-4 in the same assays. These promising results indicate that these tertiary diarylamine derivatives represent a novel class of tubulin polymerization inhibitors targeting the colchicine binding site and showing significant anti-proliferative activity.  相似文献   

3.
A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC50 values ranging from 0.049 to 38.90 μM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC50 value of 79 nM and 93 nM, respectively, whereas on colon cancer cells with an IC50 values 45 nM and 49 nM, respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G2/M phase and leads to apoptotic cell death which was confirmed by Annexin V-FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC50 value of 1.23 μM and 1.01 μM, respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin.  相似文献   

4.
A series of 1,3,4-thiadiazol-2-amide derivatives (6aw) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC50 values of 0.03 μM, 0.06 μM and 0.05 μM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC50 = 1.73 μM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.  相似文献   

5.
With the aim of investigating the influence of fluorine, in particular on the A-ring, a new series of fluoro analogues (7al) of phenstatin (3) was synthesized and tested for interactions with tubulin polymerization and evaluated for cytotoxicity on an NCI-60 human cancer cell lines panel. We have shown that the replacement of 3,4,5-trimethoxyphenyl A-ring of phenstatin with 2,4,5-trifluoro-3-methoxyphenyl unit, results in the conservation of both antitubulin and cytotoxic effect. Fluoro isocombretastatin 7k was the most effective anticancer agent in the present study and demonstrated the highest antiproliferative potential on leukemia cell lines SR (GI50 = 15 nM) and HL-60(TB) (GI50 = 23 nM) and on melanoma cell line MDA-MB-435 (GI50 = 19 nM).  相似文献   

6.
A series of novel dithiocarbamate compounds with the chalcone scaffold have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and antitubulin polymerization inhibitors. Compound 2n showed the most potent biological activity in vitro, which inhibited the growth of MCF-7 cells with IC50 of 0.04 ± 0.01 μM and the polymerization of tubulin with IC50 of 6.8 ± 0.6 μM. To understand the tubulin–inhibitor interaction and the selectivity of the most active compound towards tubulin, molecular modeling studies were performed to dock compound 2n into the colchicine binding site, which suggested probable inhibition mechanism.  相似文献   

7.
In this study, we synthesized a series of trans-indole-3-acrylamide derivatives (3ak) and investigated their activity for inhibition of cell proliferation against five human cancer cell lines (HeLa, MCF7, MDA-MB-231, Raji and HL-60) by MTT assay. Compound 3e showed significant antiproliferative activity against both the Raji and HL-60 cell lines with IC50 values of 9.5 and 5.1 μM, respectively. Compound 3e also exhibited moderate inhibitory activity on tubulin polymerization (IC50 = 17 μM). Flow cytometric analysis of cultured cells treated with 3e also demonstrated that the compound caused cell cycle arrest at the G2/M phase in HL-60 and HeLa cells. Moreover, 3e, the most active compound, caused an apoptotic cell death through the activation of caspase-3. Docking simulations suggested that 3e binds to the colchicine site of tubulin.  相似文献   

8.
A series of novel tubulin polymerization inhibitors (9a9p) have been synthesized and evaluated for their in vitro and in vivo biological activities. Among these compounds, 9e displayed strong antiproliferative activity against several tumor cell lines (IC50 = 0.15–0.62 μM). Compound 9e was also shown to arrest cells in the G2/M phase of the cell cycle and inhibit the polymerization of tubulin. Molecular docking studies suggested that 9e binds into the colchicine binding site of tubulin. In xenograft experiments, 9e exerted more potent anticancer effect than anticancer drug taxol against the H460 Human lung carcinoma in BALB/c nude mice. In summary, these findings suggest that 9e is a promising new antimitotic compound for the potential treatment of cancer.  相似文献   

9.
Twenty-five new (abiesadines A–Y, 125) and 29 known (2654) diterpenes were isolated from the aerial parts of Abies georgei. Abiesadine A (1) is a novel 8,14-seco-abietane, while abiesadine B (2) is a novel 9,10-seco-abietane. The structures of the new compounds were established on the basis of spectroscopic data analysis. Manool (52) showed the strongest effect against LPS-induced NO production in RAW264.7 macrophages with the IC50 value of 11.0 μg/mL. In another anti-inflammatory assay against TNFα-triggered NF-κB activity, (12R,13R)-8,12-epoxy-14-labden-13-ol (54) exhibited the strongest effect (IC50 = 8.7 μg/mL). For antitumor assays, pomiferin A (26) and 8,11,13-abietatriene-7α,18-diol (29) both showed the most significant activity against LOVO cells (IC50 = 9.2 μg/mL). While 7-oxocallitrisic acid (46) exhibited significant cytotoxicity against QGY-7703 tumor cells (IC50 = 10.2 μg/mL).  相似文献   

10.
As a part of our continuing study of colchicinoids as therapeutically useful antitumor drugs, thiocolchicine derivatives, including their phosphate and other water soluble salts, were synthesized and evaluated for inhibition of tubulin polymerization and for in vitro cytotoxicity. Three compounds, 7, 10, and 11, showed potent inhibition of tubulin assembly (IC50 = 0.88–1.1 μM). In addition, compound 7, a water soluble succinic acid salt of N-deacetylthiocolchicine (4), showed potent cytotoxicity against a panel of tumor cell lines, suggesting it might be a potential lead to be developed as a therapeutic antitumor agent. Compound 8, a water soluble succinic acid salt of N,N-dimethyl-N-deacetylthiocolchicine (5), showed selective activities against HCT-8 and SK-BR-3 cells. N,N-Diethyl-N-deacetylthiocolchicine (6) seemed not to be a substrate for the P-gp efflux pump, based on the similar ED50 values obtained against P-gp over-expressing KBvin (0.0146 μg/mL) cells and the parent KB (0.0200 μg/mL) cell line.  相似文献   

11.
A series of 1,2,3-triazole linked aminocombretastatin conjugates were synthesized and evaluated for cytotoxicity, inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant anticancer activity against some representative human cancer cell lines and two of the conjugates 6d and 7c displayed potent cytotoxicity with IC50 values of 53 nM and 44 nM against A549 human lung cancer respectively, and were comparable to combretastatin A-4 (CA-4). SAR studies revealed that 1-benzyl substituted triazole moiety with an amide linkage at 3-position of B-ring of the combretastatin subunit are more active compared to 2-position. G2/M cell cycle arrest was induced by these conjugates 6d and 7c and the tubulin polymerization assay (IC50 of 1.16 μM and 0.95 μM for 6d and 7c, respectively) as well as immunofluorescence analysis showed that these conjugates effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Colchicine competitive binding assay suggested that these conjugates bind at the colchicine binding site of tubulin as also observed from the docking studies. Further, mitochondrial membrane potential, ROS generation, caspase-3 activation assay, Hoechst staining and DNA fragmentation analysis revealed that these conjugates induce cell death by apoptosis.  相似文献   

12.
Tyrianthins A (1) and B (2), two new partially acylated glycolipid ester-type heterodimers were isolated from Ipomoea tyrianthina. Scammonic acid A was determined as the glycosidic acid in both monomeric units. Tyrianthin A (1) (IC50 0.24 ± 0.09 μM and Emax 81.80 ± 0.98%), and tyrianthin B (2) (IC50 0.14 ± 0.08 μM and Emax 87.68 ± 0.72%) showed significant in vitro relaxant effect on aortic rat rings, in endothelium- and concentration-dependent manners. Also, these compounds were able to increase the release of GABA and glutamic acid in brain cortex, and displayed weak antimycobacterial activity.  相似文献   

13.
A series of novel chalcone guanidine derivatives (4a4q) have been designed and synthesized, and their biological activity were also evaluated as potential antiproliferative and antitubulin polymerization inhibitors. Compound 4q showed the most potent biological activity (IC50 = 0.09 ± 0.01 μM for MCF-7 and IC50 = 8.4 ± 0.6 μM for tubulin), which is comparable to the positive controls. Docking simulation was performed to position compound 4q into the colchicine binding site to determine the probable binding model, which suggested probable inhibition mechanism.  相似文献   

14.
1-(2-(2,5-Dimethoxyphenylthio)benzylidene)semicarbazide (2a) was discovered as a potent apoptosis inducer through our cell based HTS assay. SAR study led to the discovery of a more aqueous soluble analog (2-(2,5-dimethoxyphenylthio)-6-methoxybenzylideneamino)guanidine (5e) with EC50 value of 60 nM in the caspase activation assay and GI50 value of 62 nM in the growth inhibition assay in T47D cells. Compound 5e was found to be an inhibitor of tubulin polymerization and efficacious in a MX-1 breast tumor model.  相似文献   

15.
Microwave-assisted synthesis of 23 α-cyano bis(indolyl)chalcones (6aw) and their in vitro anticancer activity against three human cancer cell lines have been discussed. Among the synthesized chalcones, compound 6n was found to be the most potent and selective against A549 lung cancer cell line (IC50 = 0.8 μM). In a preliminary mechanism of action studies some α-cyano bis(indolyl)chalcones were found to enhance tubulin polymerization suggesting these compounds could act as microtubule stabilizing agents.  相似文献   

16.
2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50 = 150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50 = 25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50 = 7.5 nM) and TNF-α production in mouse splenocytes (IC50 = 9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50 = 18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand–enzyme complex.  相似文献   

17.
Two new butyrolactones: aspernolides F (6) and G (7), together with three stigmasterol derivatives: (22E,24R)-stigmasta-5,7,22-trien-3-β-ol (1), stigmast-4-ene-3-one (2), and stigmasta-4,6,8(14), 22-tetraen-3-one (3), two meroterpenoids: terretonin A (4) and terretonin (5), and a butyrolactone derivative: butyrolactone VI (8) have been isolated from the endophytic fungus Aspergillus terreus isolated from the roots of Carthamus lanatus (Asteraceae). Their structures were determined by spectroscopic means (1D, 2D NMR, and HRESIMS), as well as optical rotation measurement and comparison with literature data. The isolated compounds were evaluated for their anti-microbial, anti-malarial, anti-leishmanial, and cytotoxic activities. Compound 1 displayed a potent activity against MRSA and C. neoformans with IC50 values of 0.96 μg/mL and 4.38 μg/mL, respectively compared to ciprofloxacin (IC50 0.07 μg/mL) and amphotericin B (IC50 0.34 μg/mL), respectively. While, 6 showed good activity against C. neoformans (IC50 5.19 μg/mL) and mild activity against MRSA (IC50 6.39 μg/mL). Moreover, 1 and 2 exhibited very good anti-leishmanial activity towards L. donovani with IC50 values of 4.61 and 6.31 μg/mL, respectively and IC90 values of 6.02 and 16.71 μg/mL, respectively.  相似文献   

18.
Recent efforts to develop cure for chronic diabetic complications have led to the discovery of potent inhibitors against aldose reductase (AKR1B1, EC 1.1.1.21) whose role in diabetes is well-evident. In the present work, two new natural products were isolated from the ariel part of Ocimum basilicum; 7-(3-hydroxypropyl)-3-methyl-8-β-O-d-glucoside-2H-chromen-2-one (1) and E-4-(6′-hydroxyhex-3′-en-1-yl)phenyl propionate (2) and confirmed their structures with different spectroscopic techniques including NMR spectroscopy etc. The isolated compounds (1, 2) were evaluated for in vitro inhibitory activity against aldose reductase (AKR1B1) and aldehyde reductase (AKR1A1). The natural product (1) showed better inhibitory activity for AKR1B1 with IC50 value of 2.095 ± 0.77 µM compare to standard sorbinil (IC50 = 3.14 ± 0.02 µM). Moreover, the compound (1) also showed multifolds higher activity (IC50 = 0.783 ± 0.07 µM) against AKR1A1 as compared to standard valproic acid (IC50 = 57.4 ± 0.89 µM). However, the natural product (2) showed slightly lower activity for AKR1B1 (IC50 = 4.324 ± 1.25 µM). Moreover, the molecular docking studies of the potent inhibitors were also performed to identify the putative binding modes within the active site of aldose/aldehyde reductases.  相似文献   

19.
We report the discovery of a series of substituted N′-(2-oxoindolin-3-ylidene)benzohydrazides as inducers of apoptosis using our proprietary cell- and caspase-based ASAP HTS assay. Through SAR studies, N′-(4-bromo-5-methyl-2-oxoindolin-3-ylidene)-3,4,5-trimethoxybenzohydrazide (3g) was identified as a potent apoptosis inducer with an EC50 value of 0.24 μM in human colorectal carcinoma HCT116 cells, more than a 40-fold increase in potency from the initial screening hit N′-(5-bromo-2-oxoindolin-3-ylidene)-3,4,5-trimethoxybenzohydrazide (2a). Compound 3g also was found to be highly active in a growth inhibition assay with a GI50 value of 0.056 μM in HCT116 cells. A group of potentially more aqueous soluble analogs were prepared and found to be highly active. Among them, compound 4e incorporating a methyl piperazine moiety was found to have EC50 values of 0.17, 0.088 and 0.14 μM in human colorectal carcinoma cells HCT116, hepatocellular carcinoma cancer SNU398 cells and human colon cancer RKO cells, respectively. Compounds 3g and 4e were found to function as inhibitors of tubulin polymerization.  相似文献   

20.
Compounds (16) isolated from the CH2Cl2 extract of Glycyrrhiza inflata and semisynthetic licochalcone A derivatives (714) were evaluated for their protein tyrosine phosphatase 1B (PTP1B) inhibitory activities. Licochalcones A (4) and E (6), each with an allyl group at position 5 in the B ring exhibited significant inhibitory effects. Licochalcone A derivative 7, the most potent among the series, had an IC50 value of 11.7 ± 2.0 μM, ca. twofold better than that of licochalcone A (4).  相似文献   

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