Design,synthesis and molecular modeling study of certain VEGFR-2 inhibitors based on thienopyrimidne scaffold as cancer targeting agents

Different series of novel thieno [2,3-d]pyrimidine derivative (9a-d,10a-f,l,m and 15a-m) were designed, synthesized and evaluated for their ability to in vitro inhibit VEGFR-2 enzyme. Also, the cytotoxicity of the final compounds was tested against a panel of 60 different human cancer cell lines by NCI. The VEGFR-2 enzyme inhibitory results revealed that compounds 10d, 15d and 15 g are among the most active inhibitors with IC₅₀ values of 2.5, 5.48 and 2.27 µM respectively, while compound 10a remarkably showed the highest cell growth inhibition with mean growth inhibition (GI) percent of 31.57%. It exhibited broad spectrum anti-proliferative activity against several NCI cell lines specifically on human breast cancer (T7-47D) and renal cancer (A498) cell lines of 85.5% and 77.65% inhibition respectively. To investigate the mechanistic aspects underlying the activity, further biological studies like flow cytometry cell cycle together with caspase-3 colorimetric assays were carried on compound 10a. Flow cytometric analysis on both MCV-7 and PC-3 cancer cells revealed that it induced cell-cycle arrest in the G0-G1phase and reinforced apoptosis via activation of caspase-3. Furthermore, molecular modeling studies have been carried out to gain further understanding of the binding mode in the active site of VEGFR-2 enzyme and predict pharmacokinetic properties of all the synthesized inhibitors.     

Dual effects of isoflavonoids from Pueraria lobata roots on estrogenic activity and anti-proliferation of MCF-7 human breast carcinoma cells

Pueraria lobata root (PLR), well known as Kudzu root, has recently become commercially available in Western dietary supplements for menopausal symptoms. The scientific basis for its action has been attributed to the action of phytoestrogens. This study aimed to investigate the estrogen-like activity of isoflavonoids isolated from P. lobata root and their safety with respect to their effect on breast cancer cell proliferation. In an E-screen assay, crude MeOH extract of PLR significantly increased the proliferation of MCF-7 cells in a concentration-dependent manner. Among the four fractions obtained by solvent fractionation of MeOH extract, the n-BuOH fraction had significant estrogen-like activities at all concentrations tested. Phytochemical analysis of the n-BuOH fraction led to the isolation of 10 isoflavones (1–10), among which genistein (10) had significant estrogen-like activities at all concentrations tested. These activities were significantly enhanced by treatment with genistein and 17β-estradiol compared with 17β-estradiol alone, and this effect was mediated by decreased expression of estrogen receptor (ER)α and phospho-ERα in MCF-7 cells. In a cell cytotoxicity assay, genistein (10) exhibited significant cytotoxicity in both ER-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells. This cytotoxicity was characterized by the induction of apoptotic cells stained with annexin V conjugated with Alexa Fluor 488 and involved activation of mitochondria-independent and -dependent apoptosis pathways in MCF-7 cells. Our results demonstrated that genistein (10) has estrogen-like effects dependent on ER pathway activation and anti-proliferative effects mediated by the apoptosis pathway rather than the ER pathway in MCF-7 breast cancer cells.     

Assessing the Effect of the Best Treatment. A Non-parametric Inference Problem

For patients of a certain type, a number of treatments are available. The effect of each such treatment is assumed to be described by a shift model; it is, however, admitted that there may be an interaction between patient and treatment, meaning in particular that the treatment which is best for one patient is not necessarily best for another. The problem is the following: if each patient is given the treatment which is optimal for that particular patient, will this produce a significant effect and, if so, how large is the effect?     

The influence of fire on the phenological behaviour of Mediterranean plant species in Bas-Languedoc (southern France)

Fire is an ancient ecological factor influencing the Mediterranean vegetation of southern France. The study was carried out on three areas to determine the phenological behaviour of plants with regard to fire. First we studied the flowering responses of perennials in relation to the time since fire: in a Quercus coccifera garrigue most species flower during the year following burning. In comparing species by species between burned and unburned areas most species did not show major differences in the phenological stages. However, fire did increase the number of inflorescences of grasses. A phenological synthesis showed that differences at the community level existed for the flowering stages between the burned areas and the unburned control sites during the first and second years following fire. The growth of some woody species was also studied; the elongation and growth of the plants were biggest during the first or second year after fire. The lack of differences in phenological response between burned and unburned plants may be an adaptive trait to fire.     

Modeling revealed circular dichroism for quinacrine in the presence of heparin

A simple model is presented that accounts for revealed circular dichroism signals that are observed as a function of enantiopreferential drug binding to a chiral selector. According to this model, the intensity of such signals depends heavily on the differences in enantiomer-selector association constants as well as the differences in bound vs. unbound molar ellipticity values for the chromophore containing species. The proposed model is supported by circular dichroism and capillary electrophoresis results obtained using quinacrine, a tricyclic, antimalarial drug, and heparin, a highly-sulfated glycosaminoglycan. This strategy also explores the role that revealed circular dichroism may play in the optical activity observed for some drugs in the presence of heparin, as has previously been illustrated for chiral drugs in the presence of DNA.     

川西盆周丘陵地区油菜作物生态效应的初步探讨

名山县位于东经103°08′,北纬30°06′,是四川省商品粮油基地县之一,属川西盆周丘陵地区。年平均气温15.5℃,日照1052.0小时,降雨量1519.9mm,一年两熟,能满足油菜全生育期的需要。全县油菜发展较快,1989年较1983年种植面积扩大了33.91%,达到6000ha;总产增加30.35%,达到5958.1t。     

Contrasting patterns in elevational diversity between microorganisms and macroorganisms

Aim Data and analyses of elevational gradients in diversity have been central to the development and evaluation of a range of general theories of biodiversity. Elevational diversity patterns have, however, been severely understudied for microbes, which often represent decomposer subsystems. Consequently, generalities in the patterns of elevational diversity across different trophic levels remain poorly understood. Our aim was to examine elevational gradients in the diversity of macroinvertebrates, diatoms and bacteria along a stony stream that covered a large elevational gradient. Location Laojun Mountain, Yunnan province, China. Methods The sampling scheme included 26 sites spaced at elevational intervals of 89 m from 1820 to 4050 m elevation along a stony stream. Macroinvertebrate and diatom richness were determined based on the morphology of the specimens. Taxonomic richness for bacteria was quantified using a molecular fingerprinting method. Over 50 environmental variables were measured at each site to quantify environmental variables that could correlate with the patterns of diversity. We used eigenvector‐based spatial filters with multiple regressions to account for spatial autocorrelation. Results The bacterial richness followed an unexpected monotonic increase with elevation. Diatoms decreased monotonically, and macroinvertebrate richness showed a clear unimodal pattern with elevation. The unimodal richness pattern for macroinvertebrates was best explained by the mid‐domain effect (r² = 0.72). The diatom richness was best explained by the variation in nutrient supply, and the increase in bacterial richness with elevation may be related to an increased carbon supply. Main conclusions We found contrasting patterns in elevational diversity among the three studied multi‐trophic groups comprising unicellular and multicellular aquatic taxa. We also found that there may be fundamental differences in the mechanisms underlying these species diversity patterns.     

Effect of propranolol and cycloheximide on the ethanol-induced increase in liver tryptophan oxygenase activity in starved rats

Increased supply of trytophan to the liver, resulting from the lipolytic action of ethanol, is suggested to be responsible for the increased activity of liver tryptophan oxygenase after ingestion of a single large dose of ethanol. This hypothesis was tested using an antilipolytic drug, propranolol, prior to ethanol treatment. It was found that, while propronolol did inhibit the ethanol-induced increase in blood unesterified fatty acids and free tryptophan concentrations it did not prevent the activation of tryptophan oxygenase by ethanol. In another experiment, where cycloheximide was used to block protein synthesis, it was found that increased protein synthesis rather than decreased protein degradation is probably responsible for the accumulation of liver tryptophan oxygenase after ethanol ingestion.     

The gelling of κ-carrageenan in light and heavy water

Gels of κ-carrageenan were prepared in H₂O and D₂O. Rheological measurements revealed that in heavy water the elastic modulus is substantially higher. From the rheological view point, this result indicates the formation of a higher number of physical-crosslinking points in the structure of the gel. These crosslinking points are mainly associated with the aggregation of the double-helix of the κ-carrageenan, which is enhanced in D₂O. The thermal stability of the gels in both solvents (relative to the sol-gel transition) was also investigated by using polarimetric measurements (to measure the relative fraction of helix-coil) and micro-differential scanning calorimetry (micro-DSC). The results obtained using these techniques are very consistent and allow us to propose a model to explain the differences for the gels formed in light and heavy water based on the degree of double-helix aggregation.