Compounds that suppress cancer cells and exhibit antitumor activity

The present invention provides compounds S3I-201.1066 (Formula 1) and S3I-201.2096 (Formula 2) as selective Stat3 binding agents that block Stat3 association with cognate receptor pTyr motifs, Stat3 phosphorylation and nuclear translocation, Stat3 transcriptional function, and consequently induced Stat3-specific antitumor cell effects in vitro and antitumor response in vivo

Compounds that suppress cancer cells and exhibit antitumor activity (US)

The present invention provides compounds S3I-201.1066 (Formula 1) and S3I-201.2096 (Formula 2) as selective Stat3 binding agents that block Stat3 association with cognate receptor pTyr motifs, Stat3 phosphorylation and nuclear translocation, Stat3 transcriptional function, and consequently induced Stat3-specific antitumor cell effects in vitro and antitumor response in vivo

Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of stat proteins (US)

In one aspect, the invention relates to substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs, derivatives thereof, and related compounds, which are useful as inhibitors of STAT protein activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a STAT protein activity dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention

Performance-Based Conditionality: A European Perspective

For several years, the conditionality underpinning budgetary support to developing countries has been the object of severe criticism. This criticism has led to the belief that the “ownership of policies” by the recipient country governments is essential for the effective implementation of economic reform programmes. To this end, it has been suggested that traditional conditionality based on policy measures be replaced by a conditionality in which aid is based on performance outcomes. In this spirit, the European Commission has reformed its adjustment aid. The present article provides an assessment of this experiment based on the experiences in Benin, Burkina Faso, Madagascar and Uganda. It demonstrates the danger of a shift towards intermediate indicators, which are too distant from the final impact of the policies, and suggests several improvements to implement genuine performance-based conditionality.Conditionality, developing countries, fiscal policy, Aid

Mimicking protein environments with bioinorganic models

Through the design and application of a novel modular synthetic strategy, a diverse family of phosphate receptors has been synthesised. The receptors were based around a complexed metal centre such as zinc (II) or copper (II) within a polyazamacrocycle framework. The initial design was to couple the polyazamacrocycle directly to a crown ether system to give a heteroditopic scaffold where the two components were in close proximity to each other. Due to the synthetic difficulties encountered, a novel approach was developed, whereby the use of an amino acid linker was employed to couple the two species. The modular approach successfully allowed the variation of the metal centre through incorporation of different sized polyazamacrocycles. In the first instance we used a four-nitrogen donor host, cylen, to chelate zinc and in the second we attached a smaller triazamacrocycle, tacn to complex copper metal. The linker was changed to allow variations in polarity, functionality and structure through the selection of specific backbone residues. The synthesis and characterisation of glycine, aminodiacetic acid and glutamic acid derivatives proved that the methodology was effective and viable for a number of different linkers with varying structure. The use of iminodiacetic acid enabled the coupling of two cyclen metal hosts which enabled the synthesis of a bimetallic zinc complex and a novel tritopic system. Most importantly, the artificial receptors that we have created were shown to be excellent hosts for phosphate moieties. The proposed mode of binding in our systems was entropically driven through the efficient desolvation of the crown ether cavity upon phosphate binding. The interactions were in general, endothermic (+DH°) which was assigned to the reorganisation of solvent molecules upon expulsion which is in agreement with a growing body of evidence in the literature. Through isothermal titration calorimetry, 1H NMR and UV/vis titration experiments, we were able to determine that the ditopic systems acted as ion pair receptors. The binding of one ion affected the affinity of the ion partner. In the case of ZnL1.(OTf)2 it was shown that the individual binding of the cation is negligible but in the presence of phosphate the cation exerts a positive influence on the binding of the anion. We were able to calculate through simple control experiments that the binding of inorganic phosphate with a number of different metal counter ions exhibited positive cooperativity. This is one of the first examples of positive cooperativity between ion pairs in an aqueous environment at physiological pH

Nanostructural changes in cell wall pectins during strawberry fruit ripening assessed by atomic force microscopy

Rapid loss of firmness occurs during strawberry (Fragaria × ananassa Duch) ripening, resulting in a short shelf life and high economic losses. The disassembly of cell walls is considered the main responsible for fruit softening, being pectins extensively modified during strawberry ripening (Paniagua et al. 2014). Atomic force microscopy allows the analysis of individual polymer chains at nanostructural level with a minimal sample preparation (Morris et al., 2001). The main objective of this research was to compare pectins of green and red ripe strawberry fruits at the nanostructural level to shed light on structural changes that could be related to softening. Cell walls from strawberry fruits were extracted and fractionated with different solvents to obtain fractions enriched in a specific component. The yield of cell wall material, as well as the amount of the different fractions, decreased in ripe fruits. CDTA and Na2CO3 fractions underwent the largest decrements, being these fractions enriched in pectins supposedly located in the middle lamella and primary cell wall, respectively. Uronic acid content also decreased significantly during ripening in both pectin fractions, but the amount of soluble pectins, those extracted with phenol:acetic acid:water (PAW) and water increased in ripe fruits. Monosaccharide composition in CDTA and Na2CO3 fractions was determined by gas chromatography. In both pectin fractions, the amount of Ara and Gal, the two most abundant carbohydrates, decreased in ripe fruits. The nanostructural characteristics of CDTA and Na2CO3 pectins were analyzed by AFM. Isolated pectic chains present in the CDTA fraction were significantly longer and more branched in samples from green fruits than those present in samples obtained from red fruit. In spite of slight differences in length distributions, Na2CO3 samples from unripe fruits displayed some longer chains at low frequency that were not detected in ripe fruits. Pectin aggregates were more frequently observed in green fruit samples from both fractions. These results support that pectic chain length and the nanostructural complexity of the pectins present in CDTA and Na2CO3 fractions diminish during strawberry fruit development, and these changes, jointly with the loss of neutral sugars, could contribute to the solubilization of pectins and fruit softening. Paniagua et al. (2014). Ann Bot, 114: 1375-1383 Morris et al. (2001). Food Sci Tech 34: 3-10 This research was supported by FEDER EU Funds and the Ministerio de Educación y Ciencia of Spain (grant reference AGL2011-24814)Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Unravelling the nanostructure of strawberry fruit pectins by atomic force microscopy

Atomic force microscopy (AFM) allows the analysis of individual polymers at nanostructural level with a minimal sample preparation. This technique has been used to analyse the pectin disassembly process during the ripening and postharvest storage of several fleshy fruits. In general, pectins analysed by AFM are usually visualized as isolated chains, unbranched or with a low number of branchs and, occasionally, as large aggregates. However, the exact nature of these structures is unknown. It has been suggested that pectin aggregates represent a mixture of rhamnonogalacturonan I and homogalacturonan, while isolated chains and their branches are mainly composed by polygalacturonic acid. In order to gain insight into the nature of these structures, sodium carbonate soluble pectins from ripe strawberry (Fragaria x ananassa, Duch.) fruits were subjected to enzymatic digestion with endo-Polygalacturonase M2 from Aspergillus aculeatus, and the samples visualized by AFM at different time intervals. Pectins isolated from control, non-transformed plants, and two transgenic genotypes with low level of expression of ripening-induced pectinase genes encoding a polygalacturonase (APG) or a pectate lyase (APEL) were also included in this study. Before digestion, isolated pectin chains from control were shorter than those from transgenic fruits, showing number-average (LN) contour length values of 73.2 nm vs. 95.9 nm and 91.4 nm in APG and APEL, respectively. The percentage of branched polymers was significantly higher in APG polyuronides than in the remaining genotypes, 33% in APG vs. 6% in control and APEL. As a result of the endo-PG treatment, a gradual decrease in the main backbone length of isolated chains was observed in the three samples. The minimum LN value was reached after 8 h of digestion, being similar in the three genotypes, 22 nm. By contrast, the branches were not visible after 1.5-2 h of digestion. LN values were plotted against digestion time and the data fitted to a first-order exponential decay curve, obtaining R2 values higher than 0.9. The half digestion time calculated with these equations were similar for control and APG pectins, 1.7 h, but significantly higher in APEL, 2.5 h, indicating that these polymer chains were more resistant to endo-PG digestion. Regarding the pectin aggregates, their volumes were estimated and used to calculate LN molecular weights. Before digestion, control and APEL samples showed complexes of similar molecular weights, 1722 kDa, and slightly higher than those observed in APG samples. After endo-PG digestion, size of complexes diminished significantly, reaching similar values in the three pectin samples, around 650 kDa. These results suggest that isolated polymer chains visualized by AFM are formed by a HG domain linked to a shorter polymer resistant to endo-PG digestion, maybe xylogalacturonan or RG-I. The silencing of the pectate lyase gene slightly modified the structure and/or chemical composition of polymer chains making these polyuronides more resistant to enzymatic degradation. Similarly, polygalacturonic acid is one of the main component of the aggregates.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

AFM study of strawberry pectin nanostructure and its relevance on fruit texture

Atomic force microscopy (AFM) has been used to characterize the nanostructure of cell wall pectins during strawberry fruit growth and ripening, as well as in transgenic fruits with pectinase genes downregulated. This technique allows the imaging of individual polymers at high magnification with minimal sample preparation. AFM studies during fruit development show that pectin size, ramification and aggregation is reduced in ripe fruits. Additionally, transgenic lines with different pectinase genes downregulated (polygalacturonase, pectate lyase and B-galactosidase) also show a more complex pectin nanostructure, including longer chains, higher branching degree and larger presence of aggregates. In all those cases the higher pectin complexity at nanoscale correlates with a reduced softening in strawberry fruits at macroscale level. Globally, our results support the key role of pectins in fruit structure and highlights the use of AFM as a powerful tool to gain insights about the bases of textural fruit quality not only in strawberry, but also in other commercial crops.AGL2017-86531-C2-1-R, Ministerio de Economía, Industria y Competitividad of Spain and FEDER EU funds. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech