Design, synthesis and antiproliferative activities of biarylolefins based on polyhydroxylated and carbohydrate scaffolds

A series of diversely substituted biarylolefins based on carbohydrate and dihydroxyethylene scaffolds were synthesized and evaluated for antiproliferative activity against a panel of human tumor cell lines. Among the thirty-five yet unknown biarylolefins prepared, six displayed potent antiproliferative activities with IC₅₀ values in the micromolar and submicromolar range. As a new type of antiproliferative agent, the most potent compound 26 showed an IC₅₀ value of 70 nM against SK-OV3 cell line (ovarian cancer). All the synthesized compounds exhibited a poor or modest tubulin polymerization inhibitory activity suggesting another mode of action for these compounds. Molecular docking simulations to the colchicine binding site of tubulin of representative compounds have been used to explain the lack of activity as inhibitors of tubulin polymerization.     

Novel imidazo[4,5-b]pyridine and triaza-benzo[c]fluorene derivatives: synthesis, antiproliferative activity and DNA binding studies

In the present paper, we have described the synthesis and biological activity of the novel derivatives of imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes (7-21, 24-26, 28-29). A preponderance of these compounds exerted strong cytostatic effects on the panel of seven human tumour cell lines in a dose-dependent manner. In particular, imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes including 2-imidazolinyl derivatives showed the most potent antitumour activity. Similarly, triaza-benzo[c]fluorenes 18 and 20 induced strong growth inhibition of tested tumour cell lines, and showed low cytotoxicity in normal human fibroblasts. DNA interaction studies of these compounds demonstrated that N-methylated 16 and 2-imidazolinyl 28 triaza-benzo[c]fluorenes bind to DNA in an intercalative mode.     

白藜芦醇治疗动脉粥样硬化关键信号通路转导机制研究进展

白藜芦醇是一种存在于多种植物中的非黄酮类多酚化合物,以其独特的药理作用成为近年来抗肿瘤、抗冠心病治疗等方面的研究热点。白藜芦醇可以增加AMPK通路的激活,调节新陈代谢率,降低血脂;也可通过抑制MAPK和mTOR通路的激活,减少血管内皮细胞增殖以及炎性因子的释放,保护血管内皮细胞,从而发挥抗氧化抗增殖作用,在动脉粥样硬化等心血管疾病防治方面有广阔的应用前景。     

The possible mechanisms of the antiproliferative effect of fullerenol,polyhydroxylated C60, on vascular smooth muscle cells

1. The possible mechanisms of the antiproliferative effect of polyhydroxylated fullerene (fullerenol), a novel free radical trapper, were studied in rat vascular smooth muscle cells (A7r5 cells) and compared with the effect of ascorbic acid.
2. Fullerenol-1 and ascorbic acid inhibited the proliferative responses in a number of cells, including rat aortic smooth muscle cells (A7r5 cells), human coronary artery smooth muscle cells, and human CEM lymphocytes (CEM cells) in a concentration dependent manner.
3. At the concentration range of 10⁻⁶ to 10⁻² M, fullerenol-1 and ascorbic acid concentration-dependently inhibited the proliferative responses stimulated by serum in A7r5 cells. Fullerenol-1 was more potent than ascorbic acid.
4. The production of O₂⁻ induced by alloxan, a diabetogenic compound, was reduced by fullerenol-1 (10⁻⁴ M) in the presence of A7r5 cells.
5. The cytosolic protein kinase C activity of A7r5 cells stimulated by phorbol ester was reduced by 10⁻³ M fullerenol-1, but not ascorbic acid (10⁻⁴–10⁻² M) and fullerenol-1 at lower concentrations (10⁻⁶–10⁻⁴ M).
6. In contrast, the membraneous protein tyrosine kinase activity of A7r5 cells stimulated by foetal calf serum was significantly reduced by fullerenol-1 (10⁻⁶–10⁻³ M) and ascorbic acid (10⁻⁴–10⁻² M). Again, the inhibitory activity of fullerenol-1 was greater than that of ascorbic acid.
7. Our results demonstrate that fullerenol-1 and ascorbic acid exhibit inhibitory effects on transduction signals in addition to their antioxidative property. It is suggested that the antiproliferative effect of fullerenol-1 on vascular smooth muscle cells may partly be mediated through the inhibition of protein tyrosine kinase.

     

Possibility of enterohepatic recycling of ketoprofen in dogs

Ketoprofen is mainly cleared by glucuronidation. The rate of glucuronidation of this compound has been demonstrated to be greater in dog than in human liver microsomes. Dog is the most common secondary nonprimate species used in drug metabolism studies in the pharmaceutical industry. Therefore, this study was undertaken to provide valuable information to pharmaceutical companies using dog as a model species for pharmacokinetic analyses when differences in glucuronidation occur across species for therapeutic drugs known to be extensively glucuronidated. The pharmacokinetics of ketoprofen was investigated after intravenous (0.27, 0.57 and 1.10 mg/kg) and oral administration of ketoprofen ( approximately 10 mg/100 ml) of the racemate in dogs. Serial blood samples were collected at timed intervals for 7 and 24h following intravenous and oral administration of the dose, respectively, and concentrations in plasma were determined by a sensitive and specific HPLC method. By comparing the AUC0-infinity following oral and intravenous administrations, ketoprofen bioavailability was approximately 100%. A possibility of enterohepatic cycling of ketoprofen in dogs was proposed because of multiple peak phenomenon in the concentration-time profiles after intravenous and oral dosing was observed.     

FCY-302, a Novel Small Molecule,Induces Apoptosis in Leukemia and Myeloma Cells by Attenuating Key Antioxidant and Mitochondrial Enzymes

Arylidene analogs are well proven for biological activities. FCY-302, a novel small molecule belonging to this class, was screened for its biological efficacy in leukemia and myeloma cells. FCY-302 selectively inhibited proliferation of cancer cells with GI50 values of 395.2 nM, 514.6 Nm, and 642.4 nM in HL-60, Jurkat, and RPMI-8226 cells, respectively. The compound also increased sub-G0 peak in the cancer cell cycle and favored apoptosis determined by annexin V assay. The compound decreased the antiapoptotic Bcl-2 levels and increased proapoptotic Bax proteins in leukemia and myeloma cell lines. FCY-302 attenuated the mitochondrial membrane-bound Na⁺ /K⁺ ATPase, Ca²⁺ ATPase, and Mg²⁺ ATPase enzyme activities and significantly decreased activities of antioxidant enzymes like SOD, CAT, G_R, and GST in all the three cancer cells tested. Our findings suggest that FCY-302 inhibits the proliferation of leukemia and myeloma cancer cells by altering key mitochondrial and antioxidant enzymes, eventually driving them to apoptosis. These results drive focus on FCY-302 and its analogs to be developed as potential small molecules with bioactivities against cancer.     

In Vitro Cytotoxic Activity of Clinacanthus nutans Leaf Extracts Against HeLa Cells

Objective: This study was conducted to investigate the antiproliferative activity of extracts of Clinacanthus nutansleaves against human cervical cancer (HeLa) cells. Methods: C. nutans leaves were subjected to extraction using 80%methanol or water. The methanol extract was further extracted to obtain hexane, dichloromethane (DCM), and aqueousfractions. The antiproliferative activity of the extracts against HeLa cells was determined. The most cytotoxic extractwas furthered analyzed by apoptosis and cell cycle assays, and the phytochemical constituents were screened by gaschromatography-mass spectrometry (GC-MS). Results: All of the extracts were antiproliferative against HeLa cells, andthe DCM fraction had the lowest IC50 value of 70 μg/mL at 48 h. Microscopic studies showed that HeLa cells exposedto the DCM fraction exhibited marked morphological features of apoptosis. The flow cytometry study also confirmedthat the DCM fraction induced apoptosis in HeLa cells, with cell cycle arrest at the S phase. GC-MS analysis revealedthe presence of at least 28 compounds in the DCM fraction, most of which were fatty acids. Conclusion: The DCMfraction obtained using the extraction method described herein had a lower IC50 value than those reported in previousstudies that characterized the anticancer activity of C. nutans against HeLa cells.     

The Anti-Proliferative and Pro-Apoptotic Properties of Ethanol Plectranthus amboinicus (Lour.) Spreng. Leaves Ethanolic Extract Nanoparticles on T47D Cell Lines

Objectives: Plectranthus amboinicus (Lour.) Spreng. is a plant which has the potential as an anti-cancer agent. Toenhance the bioavailability of an extract, it is necessary to transform the extract into nanoparticles. This research aimedto create nanoparticles of the extract and investigate the anti-proliferative and pro-apoptosis effects on T47D breastcancer cell lines. Materials and Methods: The extraction with ethanol was performed using maceration method. Thenanoparticles were prepared by using the ionic gelation method. Cytotoxic assay method evaluation of the proliferationof T47D cell line (using doubling time) was carried out using the MTT assay. Apoptosis was observed using the flowcytometry assay. Results: Treatment with Plectranthus amboinicus (Lour.) Spreng. ethanolic extract nanoparticles(PAEEN) inhibited the proliferation of T47D cell lines after 48 hours and 72 hours of incubation at concentrations of22.3 μg/mL, 44.6 μg/mL, and 89.2 μg/mL. The viable cells were 93%, 86%, 54% (48 hours), and 98%, 71%, 57%(72 hours), respectively. The nanoparticles of extract also induced apoptosis at concentrations of ¼ IC50 (2.16%), ½IC50 (1.57%), and IC50 (2.43%). Conclusion: PAEEN exhibits the anti-proliferative effect on T47D breast cancer cellsvia apoptosis. Further study is required to confirm the mechanism of PAEEN in the cell cycle arrest and apoptosisinduction on T47D cells.     

Synthesis of amide and urea derivatives of benzothiazole as Raf-1 inhibitor

A series of amide and urea derivatives of benzothiazole have been synthesized and evaluated for their antiproliferative profile in human SK-Hep-1 (liver), MDA-MB-231 (breast), and NUGC-3 (gastric) cell lines. Among them, compounds 1-2, 16-18, 23, and 25-26 had potent to moderate inhibitory activities. Further these compounds were investigated for their ability to inhibit Raf-1 activity.