Synthesis of Combretastatin A-4 and 3 0 -Aminocombretastatin A-4 derivatives with Aminoacid Containing Pendants and Study of their Interaction with Tubulin and as Downregulators of the VEGF, hTERT and c-Myc Gene Expression

Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3 0 -aminocombretastatin A-4 (AmCA-4) have shown promising antitumor activities. In this study, a range of CA-4 and AmCA-4 derivatives containing amino acid pendants have been synthesized in order to compare their biological actions with those of their parent compounds. Thus, inhibition of cell proliferation on tumor cell lines HT-29, MCF-7 and A-549, as well as on the nontumor cell line HEK-273; in vitro tubulin polymerization; mitotic cell arrest; action on the microtubule cell network and inhibition of VEGF, hTERT, and c-Myc genes have been evaluated. Some AmCA-4 derivatives bearing L-amino acids exhibited inhibition of cell proliferation at low nanomolar levels exceeding the values shown by AmCA-4. Furthermore, while CA-4 and AmCA-4 derivatives do not show significant effects on the in vitro tubulin polymerization and cell cycle arrest, some selected CA-4 and AmCA-4 derivatives are able to cause total depolymerization of the microtubule network on A-549 cells. The best results were obtained in the inhibition of gene expression, particularly on the VEGF gene, in which some AmCA-4 derivatives greatly exceeded the inhibition values achieved by the parent compound

Una discusión sobre la realidad y la teoría del capitalismo hoy: América Latina, señal de advertencia

La necesidad de cambiar el sistema del capital es un debate permanente ya que a pesar de lo que digan algunos de sus ideólogos hay un hecho esencial, y es que este sistema capitalista es un sistema histórico, de la misma manera que lo fueron otros sistemas históricos anteriores. Si antes se discutía sobre la esclavitud o sobre la servidumbre, hoy se discute sobre el asalariado, y ello da pié a lo que dice el Manifiesto Comunista cuando señala que el obrero de hoy (época de la revolución industrial iniciada en Inglaterra) es el esclavo moderno. Se trata de una figura literaria, pero que implica ya la concepción de las clases sociales, (ricos y pobres) y de las luchas sociales que este tipo de sociedad clasista significa

Synthesis and Biological Evaluation of a-Tubulin-Binding Pironetin Analogues with Enhanced Lipophilicity

The preparation of four new lipophilic analogues of the natural pyrone pironetin is described. The nine-carbon side chain of the latter has been replaced in one analogue by a 4-phenylbutyl chain and in the other three analogues by long aliphatic chains of thirteen and sixteen carbons, all of them bearing two stereogenic centers. Their cytotoxic activity and their interactions with tubulin have been investigated. It has been found that all four are cytotoxic towards two either sensitive or resistant tumoral cell lines with similar IC50 values in each case, thus indicating that, like the parent natural compound, they also display a covalent mechanism of action. However, one of them operates in all likelihood through a mechanism very similar to pironetin whereas the other three seem to be cytotoxic via a different mechanism

Synthesis and Biological Evaluation As Microtubule-Active Agents of Several Tetrahydrofuran and Spiroacetal Derivatives

The stereoselective preparation of several molecules containing structural fragments of the tetrahydrofuran and spiroacetal type is described. Their degree of cytotoxicity and their interactions with tubulin have been investigated. It has been confirmed that the tetrahydrofuran derivatives are cytotoxic but, in contrast to previous reports, it has been found that the cytoxicity is not due to interactions with the microtubule network. Furthermore, and also in contrast to a previous report on closely related compounds, the spiroacetal derivatives do show interactions with tubulin, even though the precise mechanism and the binding site still remain to be established

Macrofossils in Raraku Lake (Easter Island) integrated with sedimentary and geochemical records: Towards a palaeoecological synthesis for the last 34,000 years

Macrofossil analysis of a composite 19m long sediment core from Rano Raraku Lake (Easter Island) wasrelated to litho-sedimentary and geochemical features of the sediment. Strong stratigraphical patterns are shown by indirect gradient analyses of the data. The good correspondence between the stratigraphical patterns derived from macrofossil (Correspondence Analysis) and sedimentary and geochemical data (Principal Component Analysis) shows that macrofossil associations provide sound palaeolimnological information in conjunction with sedimentary data. The main taphonomic factors influencing the macrofossil assemblages are run-off from the catchment, the littoral plant belt, and the depositional environment within the basin. Five main stages during the last 34,000 calibrated years BP (calyrBP) are characterised from the lithological, geochemical, and macrofossil data. From 34 to 14.6calkyrBP (last glacial period) the sediments were largely derived from the catchment, indicating a high energy lake environment with much erosion and run-off bringing abundant plant trichomes, lichens, and mosses into the centre of Raraku Lake. During the early Holocene the infilling of the lake basin and warmer conditions favoured the growth of a littoral plant belt that obstructed terrigenous input. Cladoceran remains and Solanaceae seeds are indicative of reduced run-off and higher values of N and organic C indicate increased aquatic and catchment productivity. From 8.7 to 4.5calkyrBP a swamp occupied the entire basin. The increase of Cyperaceae seeds reflects this swamp development and, with oribatid mites and coleopteran remains, indicates a peaty environment and more anoxic conditions in Raraku. At around 4.5calkyrBP dry conditions prevented peat growth and there is a sedimentary hiatus. About 800calyrBP, peat deposition resumed. Finally, in the last few centuries, a small lake formed within the surrounding swamp. Evidence of human activity is recorded in these uppermost sediments. © 2011 Elsevier Ltd.This research was funded by the Spanish Ministry of Science and Education through the projects LAVOLTER (CGL2004-00683/BTE), GEOBILA (CGL2007-60932/BTE) and CONSOLIDER GRACCIE (CSD2007-00067) and an undergraduate grant (BES-2008-002938 to N. Cañellas-Boltà).Peer Reviewe

Synthesis and biological evaluation of truncated α-tubulin-binding pironetin analogues lacking alkyl pendants in the side chain or the dihydropyrone ring

The preparation of several new truncated analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the suppression of some of the alkyl pendants in either the side chain or the dihydropyrone ring. Their cytotoxic activity and their interactions with tubulin have been investigated. It has been found that all analogues are cytotoxic towards two either sensitive or resistant tumoral cell lines with similar IC50 values in each case, thus strongly suggesting that, like natural pironetin, they also display a covalent mechanism of action. Their cytotoxicity is, however, lower than that of the parent compound. This indicates that all alkyl pendants are necessary for the full biological activity, with the ethyl group at C-4 seemingly being particularly relevant. Most likely, the alkyl groups cause a restriction in the conformational mobility of the molecule and reduce the number of available conformations. This makes it more probable that the molecule preferentially adopts a shape which fits better into the binding point in α-tubulin

Synthesis and biological evaluation as microtubule-active agents of several tetrahydrofuran and spiroacetal derivatives

The stereoselective preparation of several molecules containing structural fragments of the tetrahydrofuran and spiroacetal type is described. Their degree of cytotoxicity and their interactions with tubulin have been investigated. It has been confirmed that the tetrahydrofuran derivatives are cytotoxic but, in contrast to previous reports, it has been found that the cytoxicity is not due to interactions with the microtubule network. Furthermore, and also in contrast to a previous report on closely related compounds, the spiroacetal derivatives do show interactions with tubulin, even though the precise mechanism and the binding site still remain to be established.Financial support has been granted by the Spanish Ministry of Education and Science (CTQ2008-02800), by the Consellería d´Empresa, Universitat i Ciencia de la Generalitat Valenciana (ACOMP09/113) and by the BANCAJA-UJI Foundation (P1-1B2002-06 and P1-1B-2008-14). The biological work has been supported in part by grants from the Spanish Ministry of Education and Science (BIO2007- 61336) and from the Comunidad de Madrid (grants S2010/ BMD-2457 and BIPEDD2-CM) (both to J.F.D.). We further thank the Matadero Municipal Vicente de Lucas in Segovia for providing the calf brains which were the source of tubuli

Intelligent transport systems harmonisation assessment: use case of some Spanish intelligent transport systems services

From the 1980s, new telematic technologies have meant a great evolution in several areas. In the transportation domain, their use has implied the development and implementation of several intelligent transport systems (ITS). However, these deployments were done in an isolated way. Traffic managers, public and private organisations, stakeholders and others have implemented ITS without much perspective, that is, without providing ITS as services for end users. In the last few years, several European Union (EU) funded projects have been dealing with the development of harmonised ITS services. For example, the EasyWay Project is involving most of the European countries (EU member states and others) to deploy harmonised ITS services taking into account the European citizen as the final target. In this study, an introduction of the EasyWay project is made, including the ITS concept services and the deployment guidelines for harmonisation. In November 2012, EasyWay presented a new version of DGs, which were approved with minor editorial changes. An overview on these DGs for the ITS services is presented and two real Spanish road traffic ITS services are analysed

A community challenge for a pancancer drug mechanism of action inference from perturbational profile data

The Columbia Cancer Target Discovery and Development (CTD2) Center is developing PANACEA, a resource comprising dose-responses and RNA sequencing (RNA-seq) profiles of 25 cell lines perturbed with similar to 400 clinical oncology drugs, to study a tumor-specific drug mechanism of action. Here, this resource serves as the basis for a DREAM Challenge assessing the accuracy and sensitivity of computational algorithms for de novo drug polypharmacology predictions. Dose-response and perturbational profiles for 32 kinase inhibitors are provided to 21 teams who are blind to the identity of the compounds. The teams are asked to predict high-affinity binding targets of each compound among similar to 1,300 targets cataloged in DrugBank. The best performing methods leverage gene expression profile similarity analysis as well as deep-learning methodologies trained on individual datasets. This study lays the foundation for future integrative analyses of pharmacogenomic data, reconciliation of polypharmacology effects in different tumor contexts, and insights into network-based assessments of drug mechanisms of action.Peer reviewe

Climate change facilitated the early colonization of the Azores Archipelago during medieval times

Humans have made such dramatic and permanent changes to Earth's landscapes that much of it is now substantially and irreversibly altered from its preanthropogenic state. Remote islands, until recently isolated from humans, offer insights into how these landscapes evolved in response to human-induced perturbations. However, little is known about when and how remote systems were colonized because archaeological data and historical records are scarce and incomplete. Here, we use a multiproxy approach to reconstruct the initial colonization and subsequent environmental impacts on the Azores Archipelago. Our reconstructions provide unambiguous evidence for widespread human disturbance of this archipelago starting between 700 -60/+50 and 850 -60/+60 Common Era (CE), ca. 700 y earlier than historical records suggest the onset of Portuguese settlement of the islands. Settlement proceeded in three phases, during which human pressure on the terrestrial and aquatic ecosystems grew steadily (i.e., through livestock introductions, logging, and fire), resulting in irreversible changes. Our climate models suggest that the initial colonization at the end of the early Middle Ages (500 to 900 CE) occurred in conjunction with anomalous northeasterly winds and warmer Northern Hemisphere temperatures. These climate conditions likelyinhibited exploration from southern Europe and facilitated human settlers from the northeast Atlantic. These results are consistent with recent archaeological and genetic data suggesting that the Norse were most likely the earliest settlers on the islands