Solid-phase synthesis and DNA binding studies of dichloroplatinum(II) conjugates of dicarba analogues of octreotide as a new anticancer drugs

The first dichloroplatinum(II) conjugates of dicarba analogues of octreotide , which is expected to act as a"tumour-targeting device", have been efficiently synthesized following a stepwise solid-phase approach; these compounds emulate the mechanism of cisplatin since they form a 1,2-intrastrand cross-link with two consecutive guanines of an oligonucleotide.

Membrane interaction of polymyxin B and synthetic analogues studied in biomimetic systems: implications for antibacterial action

Membrane-active antimicrobial peptides, such as polymyxin B (PxB), are currently in the spotlight as potential candidates toovercome bacterial resistance. We have designed synthetic analogs ofPxB in order to determine the structural requirements for membraneaction. Since the mechanism of action of PxB involves interaction withboth the outer membrane and the cytoplasmic membrane of Gramnegative bacteria, we have used an approach based on mimicking theouter layers of these membranes using monolayers, Langmuir-Blodgettfilms and unilamelar vesicles, and applying a battery of biophysicalmethods in order to dissect the different events of membraneinteraction. Collectively, results indicate that the PxB analogues act inthe bacterial membrane by the same mechanism than PxB, and that cationic amphipathicity determines peptide activity.

Membrane interaction of polymyxin B and synthetic analogues studied in biomimetic systems: implications for antibacterial action

Membrane-active antimicrobial peptides, such as polymyxin B (PxB), are currently in the spotlight as potential candidates toovercome bacterial resistance. We have designed synthetic analogs ofPxB in order to determine the structural requirements for membraneaction. Since the mechanism of action of PxB involves interaction withboth the outer membrane and the cytoplasmic membrane of Gramnegative bacteria, we have used an approach based on mimicking theouter layers of these membranes using monolayers, Langmuir-Blodgettfilms and unilamelar vesicles, and applying a battery of biophysicalmethods in order to dissect the different events of membraneinteraction. Collectively, results indicate that the PxB analogues act inthe bacterial membrane by the same mechanism than PxB, and that cationic amphipathicity determines peptide activity.

Expression of somatostatin receptors in human melanoma cell lines: effect of two different somatostatin analogues, octreotide and SOM230, on cell proliferation

Somatostatin analogues (SAs) are potential anticancer agents. This study was designed to investigate the expression of somatostatin receptors (SSTRs) in melanoma cells and the effect of two SAs on cell proliferation and viability. Eighteen primary and metastatic human cutaneous melanoma cell lines were treated with octreotide and SOM230. Expression of SSTR1, SSTR2, SSTR3 and SSTR5 was assessed by real-time polymerase chain reaction. Proliferation, viability and cell death were assessed using standard assays. Inhibition was modelled by mixed-effect regression. Melanoma cells expressed one or more SSTR. Both SAs inhibited proliferation of most melanoma cell lines, but inhibition was less than 50%. Neither SA affected cell viability or induced cell death. The results suggest that melanoma cell lines express SSTRs. The SAs investigated, under the conditions used in this study, did not, however, significantly inhibit melanoma growth or induce cell death. Novel SAs, combination therapy with SAs and their anti-angiogenic properties should be further investigated.

Synthesis and structure - Activity relationship study of potent cytotoxic analogues of the marine alkaloid Lamellarin D

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines, and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogs of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB- 231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data the SAR study concluded that more than 75% of the open-chain Lam-D analogs tested showed cytotoxicity in a low micromolar GI50 range.

Synthesis and antitumor activity of mechercharmycin A analogues

Several analogs of the cytotoxic thiopeptide IB-01211 or Mechercharmycin A (1) have been synthetized. The cytotoxicity of 1 and the synthetized analogs was evaluated against a panel of three human tumor cell lines. Thiopeptide 1 and the most active derivatives, 2 and 3c, were chosen for further studies like effects on cell cycle progression and induction of apoptosis. Interestingly, the inhibition of cell division and activation of a programmed cell death by apoptosis was detected.

Synthesis and structure - Activity relationship study of potent cytotoxic analogues of the marine alkaloid Lamellarin D

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines, and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogs of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3- carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB- 231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data the SAR study concluded that more than 75% of the open-chain Lam-D analogs tested showed cytotoxicity in a low micromolar GI50 range.

Síntesi estereoselectiva d'anàlegs ciclobutènics d'L-nucleòsids

En els darrers 30 anys, els anàlegs de nucleòsids han estat una part essencial de la teràpia antiviral. Més recentment, els anàlegs carbocíclics de nucleòsids s'han convertit en importants objectius pel desenvolupament de nous agents terapèutics antivirals i antitumorals, en tant que l'absència de l'enllaç N-glicosídic els confereix una major estabilitat davant l'acció de les fosforilases. Per altra banda, s'ha descrit que alguns nucleòsids de configuració L presenten, en alguns casos, una bona activitat antiviral, una major estabilitat metabòlica i una toxicitat inferior a la dels seus homòlegs de configuració natural. El present treball planteja la síntesi estereoselectiva de derivats ciclobutènics de L-nucleòsids com a agents terapèutics, susceptibles de presentar una major activitat antiviral i una menor toxicitat que els agents actuals. Per assolir aquest objectiu, s'ha construït l'anell ciclobutènic mitjançant una reacció de fotocicloaddició [2+2]. Al mateix temps, s'ha desenvolupat un estudi de la influència del dissolvent en la reacció de fotocicloaddició [2+2] d'enones a alquens halogenats. A més, s'han estudiat diverses condicions de treball per dur a terme la reacció de deshalogenació dels derivats clorats preparats amb la metodologia anterior, utilitzant Zn com a reductor i amb un sistema d'escalfament per microones com a substituent dels mètodes d'escalfament convencionals. Aquest estudi ha permès disminuir notablement el temps d'aquesta reacció, passant de 7 hores a 20 minuts. Les condicions òptimes d'ambdues reaccions determinades amb aquests estudis han permès preparar l'intermedi clau per a la introducció de les bases nitrogenades, essent aquest un potencial precursor dels anàlegs ciclobutènics de nucleòsids, així com sintetitzar el primer producte de la ruta sintètica dissenyada que presenta la base nitrogenada a la seva estructura.

Obtenció de nous anàlegs amb activitat brassinoesteroide mitjançant modelització molecular i síntesi

Els brassinoesteroides són productes naturals que actuen com a potents reguladors del creixement vegetal. Presenten aplicacions prometedores en l’agricultura degut a que, aplicats exògenament, augmenten la qualitat i la quantitat de les collites. Ara bé, el seu ús s’ha vist restringit degut a la seva costosa obtenció. Aquest fet ha motivat la recerca de nous compostos actius més assequibles. En aquest projecte es planteja el disseny i obtenció de nous anàlegs seguint diferents estratègies que impliquen tant l’ús de mètodes de modelització molecular com de síntesi orgànica. La primera d’aquestes estratègies consisteix en buscar compostos actius en bases de dades de compostos comercials a través de processos de Virtual Screening desenvolupats amb mètodes computacionals basats en Camps d’Interacció Molecular. Així, es van establir i interpretar models de Relacions Quantitatives Estructura-Activitat (QSAR) emprant descriptors independents de l’alineament (GRIND) i, amb col•laboració amb la Universitat de Perugia, aquest criteri de cerca es va ampliar amb l’aplicació de descriptors FLAP de nova generació. Una altra estratègia es va basar en intentar substituir l’esquelet esteroide dels brassinoesteroides per una estructura equivalent, fixant com a cadena lateral el grup (R)-hexahidromandelil. S’han aplicat dos criteris: mètodes computacionals basats en models QSAR establerts amb descriptors GRIND i també en la metodologia SHOP (scaffold hopping), i, per altra banda, anàlegs proposats racionalment a partir d’un estudi efectuat sobre disruptors endocrins no esteroïdals. Sobre les estructures trobades s’hi va unir la cadena lateral comercial esmentada per via sintètica, en la qual s’ha hagut de fer un èmfasi especial en grups protectors. En total, 49 estructures es proposen per a ser obtingudes sintèticament. També s’ha treballat en l’obtenció un agonista derivat de l’hipotètic antagonista KM-01. Totes les molècules candidates, ja siguin comercials o obtingudes sintèticament, estant sent avaluades en el test d’inclinació de la làmina d’arròs (RLIT).

CODAMAT: a modern analogue techinque for compositional data

The quantitative estimation of Sea Surface Temperatures from fossils assemblages is afundamental issue in palaeoclimatic and paleooceanographic investigations. TheModern Analogue Technique, a widely adopted method based on direct comparison offossil assemblages with modern coretop samples, was revised with the aim ofconforming it to compositional data analysis. The new CODAMAT method wasdeveloped by adopting the Aitchison metric as distance measure. Modern coretopdatasets are characterised by a large amount of zeros. The zero replacement was carriedout by adopting a Bayesian approach to the zero replacement, based on a posteriorestimation of the parameter of the multinomial distribution. The number of modernanalogues from which reconstructing the SST was determined by means of a multipleapproach by considering the Proxies correlation matrix, Standardized Residual Sum ofSquares and Mean Squared Distance. This new CODAMAT method was applied to theplanktonic foraminiferal assemblages of a core recovered in the Tyrrhenian Sea.Kew words: Modern analogues, Aitchison distance, Proxies correlation matrix,Standardized Residual Sum of Squares

Effect of expiratory flow limitation on respiratory mechanical impedance: a model study

Large phasic variations of respiratory mechanical impedance (Zrs) have been observed during induced expiratory flow limitation (EFL) (M. Vassiliou, R. Peslin, C. Saunier, and C. Duvivier. Eur. Respir. J. 9: 779-786, 1996). To clarify the meaning of Zrs during EFL, we have measured from 5 to 30 Hz the input impedance (Zin) of mechanical analogues of the respiratory system, including flow-limiting elements (FLE) made of easily collapsible rubber tubing. The pressures upstream (Pus) and downstream (Pds) from the FLE were controlled and systematically varied. Maximal flow (Vmax) increased linearly with Pus, was close to the value predicted from wave-speed theory, and was obtained for Pus-Pds of 4-6 hPa. The real part of Zin started increasing abruptly with flow (V) >85%Vmax and either further increased or suddenly decreased in the vicinity of V¿max. The imaginary part of Zin decreased markedly and suddenly above 95%Vmax. Similar variations of Zin during EFL were seen with an analogue that mimicked the changes of airway transmural pressure during breathing. After pressure andV measurements upstream and downstream from the FLE were combined, the latter was analyzed in terms of a serial (Zs) and a shunt (Zp) compartment. Zs was consistent with a large resistance and inertance, and Zp with a mainly elastic element having an elastance close to that of the tube walls. We conclude that Zrs data during EFL mainly reflect the properties of the FLE.

Convergent Approaches for the Synthesis of the Anti-tumoral Peptide, Kahalalide F. Study of Orthogonal Protecting Groups

Kahalalide compounds are peptides that are isolated from a Hawaiian herbivorous marine species of mollusc, Elysia rufescens, and its diet, the green alga Bryopsis sp. Kahalalide F and its synthetic analogues are the most promising compounds of the Kahalalide family because they show anti-tumoral activity. Linear solid-phase syntheses of Kahalalide F have been reported. Here we describe several new improved synthetic routes based on convergent approaches with distinct orthogonal protection schemes for the preparation of Kahaladide analogues. These strategies allow a better control and characterization of the intermediates because more reactions are performed in solution. Five derivatives of Kahalalide F were synthesized using several convergent approaches.

Algorithms and cryptographic protocols using elliptic curves

En els darrers anys, la criptografia amb corbes el.líptiques ha adquirit una importància creixent, fins a arribar a formar part en la actualitat de diferents estàndards industrials. Tot i que s'han dissenyat variants amb corbes el.líptiques de criptosistemes clàssics, com el RSA, el seu màxim interès rau en la seva aplicació en criptosistemes basats en el Problema del Logaritme Discret, com els de tipus ElGamal. En aquest cas, els criptosistemes el.líptics garanteixen la mateixa seguretat que els construïts sobre el grup multiplicatiu d'un cos finit primer, però amb longituds de clau molt menor. Mostrarem, doncs, les bones propietats d'aquests criptosistemes, així com els requeriments bàsics per a que una corba sigui criptogràficament útil, estretament relacionat amb la seva cardinalitat. Revisarem alguns mètodes que permetin descartar corbes no criptogràficament útils, així com altres que permetin obtenir corbes bones a partir d'una de donada. Finalment, descriurem algunes aplicacions, com són el seu ús en Targes Intel.ligents i sistemes RFID, per concloure amb alguns avenços recents en aquest camp.

Utilización de análogos fluorados de la feromona sexual de Sesamia nonagrioides Lef. como inhibidores de su actividad biológica

Se ha estudiado el papel, como inhibidores de la acción feromonal, de determinados fluoroderivados, análogos estructurales del acetato de (Z)-l 1-hexadecenilo, componente principal de la feromona sexual del noctuido Sesamia nonagrioides Lef. Dichos compuestos fueron los análogos fluoroacetato (mono, di y trifluoroacetato de (Z)-l 1-hexadecenilo) y la trifluorometilcetona análoga [(Z)-1,1,1 -trifluoro-14-nonadecen-2-ona]. La acción inhibidora fue evaluada a partir de los resultados de actividad electrofisiológica (pruebas de electroantenograma, EAG), de estudios de comportamiento en pruebas de túnel de viento y de pruebas de capturas en campo. Los acetatos fluorados, especialmente el mono y el trifluoracetato, se mostraron como buenos inhibidores de la acción atrayente de la feromona en los tres tipos de pruebas realizadas, mientras que la trifluorometilcetona análoga mostró una actividad mucho menor.

Architectural characterization of a delta-front reservoir analogue combining ground penetrating radar and electrical resistivity tomography: Roda Sandstone (Lower Eocene, Graus-Tremp basin, Spain)

Three-dimensional reconstruction of reservoir analogues can be improved combining data from different geophysical methods. Ground Penetrating Radar (GPR) and Electrical Resistivity Tomography (ERT) data are valuable tools, since they provide subsurface information from internal architecture and facies distribution of sedimentary rock bodies, enabling the upgrading of depositional models and heterogeneity reconstruction. The Lower Eocene Roda Sandstone is a well-known deltaic complex widely studied as a reservoir analogue that displays a series of sandstone wedges with a general NE to SW progradational trend. To provide a better understanding of internal heterogeneity of a 10m-thick progradational delta-front sandstone unit, 3D GPR data were acquired. In addition, common midpoints (CMP) to measure the sandstone subsoil velocity, test profiles with different frequency antennas (25, 50 and 100MHz) and topographic data for subsequent correction in the geophysical data were also obtained. Three ERT profiles were also acquired to further constrain GPR analysis. These geophysical results illustrate the geometry of reservoir analogue heterogeneities both depositional and diagenetic in nature, improving and complementing previous outcrop-derived data. GPR interpretation using radar stratigraphy principles and attributes analysis provided: 1)tridimensional geometry of major stratigraphic surfaces that define four units in the GPR Prism, 2) image the internal architecture of the units and their statistical study of azimuth and dips, useful for a quick determination of paleocurrent directions. These results were used to define the depositional architecture of the progradational sandbody that shows an arrangement in very-high-frequency sequences characterized by clockwise paleocurrent variations and decrease of the sedimentary flow, similar to those observed at a greater scale in the same system. This high-frequency sequential arrangement has been attributed to the autocyclic dynamics of a supply-dominated delta- front where fluvial and tidal currents are in competition. The resistivity models enhanced the viewing of reservoir quality associated with cement distribution caused by depositional and early diagenetic processes related to the development of transgressive and regressive systems tracts in igh-frequency sequences.