Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Novel 2-[(benzylamino)methyl]pyrrolidine-3,4-diol derivatives as alpha-mannosidase inhibitors and with antitumor activities against hematological and solid malignancies.

Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.

Determinants of credit default swap spread: evidence from european credit derivatives market

Tämän tutkielman tavoitteena on selvittää, mitkä tekijät vaikuttavat yrityksen ja valtion velkakirjojen väliseen tuottoeroon. Strukturaalisten luottoriskin hinnoittelumallien mukaan luottoriskiin vaikuttavia tekijöitä ovat yrityksen velkaantumisaste, volatiliteetti ja riskitön korkokanta. Tavoitteena on erityisesti tutkia, kuinka hyvin nämä teoreettiset tekijät selittävät tuottoeroja ja onko olemassa muita tärkeitä selittäviä tekijöitä. Luottoriskinvaihtosopimusten noteerauksia käytetään tuottoerojen määrittämiseen. Selittävät tekijät koostuvat sekä yrityskohtaisista että markkinalaajuisista muuttujista. Luottoriskinvaihtosopimusten ja yrityskohtaisten muuttujien data on kerätty yhteensä 50 yritykselle Euroalueen maista. Aineisto koostuu kuukausittaisista havainnoista aikaväliltä 01.01.2003-31.12.2006. Empiiriset tulokset osoittavat, että strukturaalisten mallien mukaiset tekijät selittävät vain pienen osan tuottoeron muutoksista yli ajan. Toisaalta nämä teoreettiset tekijät selittävät huomattavasti paremmin tuottoeron vaihtelua yli poikkileikkauksen. Muut kuin teoreettiset tekijät pystyvät selittämään suuren osan tuottoeron vaihtelusta. Erityisen tärkeäksi tuottoeron selittäväksi tekijäksi osoittautui yleinen riskipreemio velkakirjamarkkinoilla. Tulokset osoittavat, että luottoriskin hinnoittelumalleja on kehitettävä edelleenniin, että ne ottaisivat huomioon yrityskohtaisten tekijöiden lisäksi myös markkinalaajuisia tekijöitä.

From symmetric glycerol derivatives to dissymmetric chlorohydrins

The anticipated worldwide increase in biodiesel production will result in an accumulation of glycerol for which there are insufficient conventional uses. The surplus of this by-product has increased rapidly during the last decade, prompting a search for new glycerol applications. We describe here the synthesis of dissymmetric chlorohydrin esters from symmetric 1,3-dichloro-2-propyl esters obtained from glycerol. We studied the influence of two solvents: 1,4-dioxane and 1-butanol and two bases: sodium carbonate and 1-butylimidazole, on the synthesis of dissymmetric chlorohydrin esters. In addition, we studied the influence of other bases (potassium and lithium carbonates) in the reaction using 1,4-dioxane as the solvent. The highest yield was obtained using 1,4-dioxane and sodium carbonate.

Diphenyl urea derivatives as inhibitors of transketolase: a structure-based virtual screening.

Transketolase is an enzyme involved in a critical step of the non-oxidative branch of the pentose phosphate pathway whose inhibition could lead to new anticancer drugs. Here, we report new human transketolase inhibitors, based on the phenyl urea scaffold, found by applying structure-based virtual screening. These inhibitors are designed to cover a hot spot in the dimerization interface of the homodimer of the enzyme, providing for the first time compounds with a suggested novel binding mode not based on mimicking the thiamine pyrophosphate cofactor.

Concentrations of resveratrol and derivatives in foods and estimation of dietary intake in a Spanish population: European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort

Resveratrol has been shown to have beneficial effects on diseases related to oxidant and/or inflammatory processes and extends the lifespan of simple organisms including rodents. The objective of the present study was to estimate the dietary intake of resveratrol and piceid (R&P) present in foods, and to identify the principal dietary sources of these compounds in the Spanish adult population. For this purpose, a food composition database (FCDB) of R&P in Spanish foods was compiled. The study included 40 685 subjects aged 35-64 years from northern and southern regions of Spain who were included in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort. Usual food intake was assessed by personal interviews using a computerised version of a validated diet history method. An FCDB with 160 items was compiled. The estimated median and mean of R&P intake were 100 and 933 mg/d respectively. Approximately, 32% of the population did not consume RΠ The most abundant of the four stilbenes studied was trans-piceid (53·6 %), followed by trans-resveratrol (20·9 %), cis-piceid (19·3 %) and cis-resveratrol (6·2 %). The most important source of R&P was wines (98·4 %) and grape and grape juices (1·6 %), whereas peanuts, pistachios and berries contributed to less than 0·01 %. For this reason the pattern of intake of R&P was similar to the wine pattern. This is the first time that R&P intake has been estimated in a Mediterranean country.

Utilisation of Short Term Electricity Derivatives in Industrial Energy Management

Työn päätavoite on selvittää kuinka erityisesti sähkön markkinahinnan ennustamiseen ja johdannaismarkkinoiden tietämykseen perustuva lyhyen tähtäimen sähköjohdannaisten hyödyntäminen tapahtuu teollisessa energianhallinnassa. Tätä aihetta lähestytään luomalla prosessi lyhyen tähtäimen sähköjohdannaisten hyödyntämiselle. Prosessi esitellään ja selvitetään aina lähtökohdista todelliseen kaupankäyntiin asti erillisen esimerkkitehtaan avulla.Lyhyen tähtäimen sähköjohdannaisten hyödyntäminen teollisessa energianhallinnassa perustuu pääosin tulevaisuuden odotuksiin sähkön markkinahinnan kehittymisestä sekä tehtaiden operatiiviseen tilanteeseen. Operatiiviseen tilanteeseen perustuva lyhyen tähtäimen sähköjohdannaisten kaupankäynti on pääasiassa pitkän tähtäimen suojausten sopeuttamista lyhyelle tähtäimelle sopivaksi.Hinnan ennustamisella on suuri rooli lyhyen tähtäimen sähköjohdannaisten hyödyntämisprosessissa. Työssä esitelty hinnan ennustamismalli on sopiva päivä- ja viikkotason Nord Poolin Elspot -systeemihinnan ennustamiseen. Elspot -systeemihinnan ennustamismalli on suunniteltu käytännönläheiseksi ja sen perustana ovat todelliset fysikaaliset ja mitattavat suureet. Futuurimarkkinatietämys on tarpeen lyhyen tähtäimen johdannaisia käytettäessä. Työssä tutkitaan yleisiä markkinoiden odotuksia ja futuurimarkkinoiden tietoisuuden kehittymistä koskien tulevaa vallitsevaa tilannetta. Työssä luodaan myös työkalu, mikä auttaa kaupan laatijaa muodostamaan suuntaa-antavat todennäköisyydet eri hintanäkemyksille ja paikallistamaan mahdolliset markkinoiden epätodennäköiset hintaodotukset.Kokemukset Elspot -systeemihinnan ennustamismallin soveltamisesta ovat lupaavia. Lisäksi havainnot futuurimarkkinoiden käyttäytymisestä Nord Poolissa ja muodostettu työkalu suuntaa-antavien todennäköisyyksien selvittämiseksi auttavat kaupan laatijaa päätöksenteossa. Lyhyen tähtäimen sähköjohdannaisten hyödyntäminen teollisessa energianhallinnassa on periaatteessa mahdollista esitellyn prosessin avulla, vaikka täydellinen käyttöönotto vaatisi vielä joitakin järjestelyjä. Keskittymällä tilanteisiin jotka työssä kuvatulla prosessilla ovat hoidettavissa, työssä määritellyllä menettelyllä on mahdollisuudet saavuttaa epäedullisen hintakehityksen riskin väheneminen ja parempi taloudellinen tulos teollisen energianhallinnan sähkökaupankäynnissä.

Peptide-decorated chitosan derivatives enhance fibroblast adhesion and proliferation in wound healing.

RGD peptide sequences are known to regulate cellular activities by interacting with α5β1, αvβ5 and αvβ3 integrin, which contributes to the wound healing process. In this study, RGDC peptide was immobilized onto chitosan derivative 1,6-diaminohexane-O-carboxymethyl-N,N,N-trimethyl chitosan (DAH-CMTMC) to display RGDC-promoting adhesion for enhanced wound healing. The efficiency of N-methylation, O-carboxymethylation and spacer grafting was quantitatively and qualitatively analyzed by (1)H NMR and FTIR, yielding 0.38 degree of substitution for N-methylation and >0.85 for O-carboxymethylation. The glass transition temperatures for chitosan derivatives were also studied. Peptide immobilization was achieved through sulfhydryl groups using sulfosuccinimidyl (4-iodoacetyl)amino-benzoate (sulfo-SIAB method). RGDC immobilized peptide onto DAH-CMTMC was found to be about 15.3μg/mg of chitosan derivative by amino acid analysis (AAA). The significant increase of human dermal fibroblast (HDF) viability in vitro over 7 days suggests that RGDC-functionalized chitosan may lead to enhanced wound healing (viability >140%). Moreover, bio-adhesion and proliferation assays confirmed that coatings of RGDC-functionalized chitosan derivatives exhibit in vitro wound healing properties by enhancing fibroblast proliferation and adhesion. These results showed that RGDC peptide-functionalized chitosan provides an optimal environment for fibroblast adhesion and proliferation.

Lamellarin D bioconjugates I: synthesis and cellular internalization of PEG-derivatives

Herein is reported the design and synthesis of poly(ethylene glycol) derivatives of Lamellarin D with the aim of modulating their physicochemical properties, and improving the biological activity. Mono-, di- and tri-PEG conjugates with improved solubility were obtained in 18-57% overall yields from the corresponding partially protected phenolic derivatives of Lamellarin D. Conjugates 1-9 were tested in a panel of three human tumor cell lines (MDA-MB-231 breast, A-549 lung and HT-29 colon) to evaluate their cytotoxicity. Several compounds exhibited enhanced cellular internalization, and more than 85% of the derivatives showed a lower GI50 than Lam-D. Furthermore, cell cycle arrest at G2 phase, and apoptotic cell-death pathways were determined for Lamellarin D and these derivatives.

Lamellarin D bioconjugates II: synthesis and cellular internalization of dendrimer and nuclear location signal derivatives

The design and synthesis of Lamellarin D conjugates with a nuclear localization signal peptide and a poly(ethylene glycol)-based dendrimer are described. Conjugates 1-4 were obtained in 8-84% overall yields from the corresponding protected Lamellarin D. Conjugates 1 and 4 are 1.4 to 3.3-fold more cytotoxic than the parent compound against three human tumor cell lines(MDA-MB-231 breast, A-549 lung, and HT-29 colon). Besides, conjugates 3, 4 showed a decrease in activity potency in BJ skin fibroblasts, a normal cell culture. Cellular internalization was analyzed and nuclear distribution pattern was observed for 4, which contains a nuclear localization signalling sequence.

Lamellarin D bioconjugates I: synthesis and cellular internalization of PEG-derivatives

Herein is reported the design and synthesis of poly(ethylene glycol) derivatives of Lamellarin D with the aim of modulating their physicochemical properties, and improving the biological activity. Mono-, di- and tri-PEG conjugates with improved solubility were obtained in 18-57% overall yields from the corresponding partially protected phenolic derivatives of Lamellarin D. Conjugates 1-9 were tested in a panel of three human tumor cell lines (MDA-MB-231 breast, A-549 lung and HT-29 colon) to evaluate their cytotoxicity. Several compounds exhibited enhanced cellular internalization, and more than 85% of the derivatives showed a lower GI50 than Lam-D. Furthermore, cell cycle arrest at G2 phase, and apoptotic cell-death pathways were determined for Lamellarin D and these derivatives.

Peptídeos de conformação restrita induzida pela incorporação de unidades (aza)lactâmicas

Conformational constraint is an approach which can be used to restrict the flexibility of peptide molecules and to provide information on the topographical requirements of receptors. The incorporation of conformationally constrained units in a peptide can lead to peptide analogues that present numerous advantages such as the potentialization of the pharmacological activity and the decrease of enzymatic degradation. This review discusses the peptide analogues containing a lactam or azalactam unit in their sequences. Of particular interest has been the replacement of a dipeptide motif in a peptide that simulates a beta-turn.

Enantioselective synthesis of aziridines using asymmetric transfer hydrogenation as a precursor for chiral derivatives used as bonding agent for rocket solid propellants

A rapid, expedient and enantioselective method for the synthesis of beta-hydroxy amines and monosubstituted aziridines in up to 99% e.e., via asymmetric transfer hydrogenation of a-amino ketones and cyclisation through treatment with tosyl chloride and base, is described. (1R,2R)-N-(para-toluenesulfonyl)-1,2-ethylenediamine with formic acid has been utilised as a ligand for the Ruthenium (II) catalysed enantioselective transfer hydrogenation of the ketones.The chiral 2-methyl aziridine, which is a potentially more efficient bonding agent for Rocket Solid Propellant has been successfully achieved.

Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures

The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by 'RTK swapping' by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation.