Search

Conformationally constrained dipeptoid analogues containing the type II′ β-turn mimic (2 S ,5 S ,11b R )-2-amino-3-oxohexahydroindolizino[8,7- b ]indole-5-carboxylate framework in place of the α-MeTrp residue, show high binding affinity and selectivity for CCK-A receptors, suggesting that a turn-like conformation could contribute to the bioactive conformation at this CCK receptor subtype.

The synthesis, binding to CCK receptors, and in vitro functional activity of pseudopeptide CCK-4 analogues incorporating the ( R ) or ( S ) Ψ[CH(CN)NH] peptide bond surrogate at the NIe 31 -Asp 32 or or Trp 30 -NIe 13 bonds are described. Z-TrpΨ[( S )CH(CN)NH]NIe-Asp-Phe-NH 2 retained the high CCK-B receptor binding affinity of Boc-[NIe 31 ]-CCK-4, and was a potent and selective CCK-B antagonist in the isolated guinea pig ileum.

The reaction of aminonitriles (I) with isocyanates leads to desired ureas (III) in high isolated yields, whilst crude ureas derived from aminonitriles (IV) are prone to a cyclization during chromatographic purification affording hydantoins (V).

An efficient and environmentally friendly methodology for the solvent-free synthesis of α-amino nitrile derived ureas from α-amino acid based amino nitriles has been developed. At room temperature no epimerization was observed in the resulting ureas, but under microwave heating, epimerization occurred at the chiral center bearing the cyano group.

1,2-Diamine derivatives are valuable building blocks to heterocyclic compounds and important precursors of biologically relevant compounds. In this respect, amino acid-derived β-keto esters are a suitable starting point for the synthesis of β,γ-diamino ester derivatives through a two-step reductive amination procedure with either simple amines or α-amino esters. AcOH and NaBH3CN are the additive and reducing agents of choice. The stereoselectivity of the reaction is still an issue, due to the slow imine-enamine equilibria through which the reaction occurs, affording mixtures of diastereoisomers that can be chromatographically separated. Transformation of the β,γ-diamino esters into pyrrolidinone derivatives allows the configuration assignment of the linear compounds, and constitutes an example of their potential application in the generation of molecular diversity., Spanish Ministry of Science and Innovation, SAF2009–09323 and Consolider-Ingenio CSD 2008–00005 (Spanish Ion Channel Initiative) and CSD2006–00015 (Crystallization Factory). P.P.-F. and M.T.A. thank the Consejo Superior de Investigaciones Cientıficas (CSIC) for a JAE-predoc fellowship and a JAEdoc contract, respectively, both from the Program Junta para la Ampliacion de Estudios co-financed by the ESF

13 páginas, 8 figuras y 3 tables, The hyper-arid core of the Atacama Desert in Chile is considered the driest and most life-limited place on Earth, with few habitats capable of sustaining an active microbial ecosystem. As such, it is one of the best terrestrial analogues of the extreme arid conditions on Mars, and an ideal environment to explore survival and biological adaptation strategies as the environment becomes increasingly dry. Here we show that weakly welded rhyolitic ignimbrites in this desert are abundantly colonized by endolithic cyanobacteria and associated heterotrophic bacteria. We propose that the porous ignimbrite interior provides protection from damaging UV radiation and excessive levels of visible light. Rock porosity also favors cell hydration through water retention after scarce rainfall events, even when the surrounding environment remains stubbornly dry. This is the first known example of an endolithic microbial community colonizing ignimbrite rocks in an extremely dry environment. The existence of a habitat capable of supporting abundant phototrophic and heterotrophic communities in an environment that precludes most life forms suggests that, if similar deposits are found on Mars, these should be considered important targets in the search for life. Indeed, ignimbrite rocks have been tentatively identified in Gale Crater, the landing site of the Mars Science Laboratory (MSL) mission and could be directly analyzed by its rover Curiosity, The authors thank F. Pinto, V. Souza-Egipsy and T. Carnota for technical assistance, and L. Tormo for help with the ESEM, R. Gonzalez with the FRX, M. Juanco with the XRD, and A.L. Duque and D. Gamarra with the MIP work. D. Herrera is thanked for field assistance in the Atacama Desert. We also thank A. Burton for polishing our English. This work was funded by grant CGL2010-16004 and CTM 2009-12838-C04-03 from the Spanish Ministry of Science and Innovation. A.F.D., O.A. and J.W. were supported by Grant NNX12AD61G of the NASA Exobiology program

A series of pseudodipeptide-based chiral 1,3,4,5-tetrasubstituted-2- oxopiperazines has been designed and synthesized as potential PAR1 antagonists. These highly functionalized piperazines were synthesized from aromatic and basic amino acid derived Ψ[CH(CN)NH]pseudodipeptides through a four step pathway that involves reduction of the cyano group to build the 2-oxopiperazine ring, followed by selective functionalization at the N4-, N 1-positions, and at the exocyclic moiety at position C5. This regioselective functionalization required the fine tuning of reaction conditions. All new compounds were screened as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cell lines. Some of the compounds displayed moderate PAR1 antagonist activity, while, others were cytotoxic at μM concentration. No correlation was observed between both types of activities.

The ability of a series of structures to mimic the geometric and electronic properties of an ideal γ–turn has been studied. Initially, an exhaustive conformational analysis was carried out using the molecular dynamics technique at high temperature followed by minimization. Additionally, each minimum was optimized with the semi–ab initio molecular orbital method SAM1. Then, the unique minima found have been superimposed with ideal γ–turns, classic and inverse, using the SEAL program which takes into account steric and electronic parameters for the superpositions and finally, three molecular similarity indices were determined for each superposition. These indices consider the general steric and electronic characteristics of the structures, as well as, the position of the carbon atoms that correspond to the Cαi and Cαi+2 in the peptide chain.

(−)-Cuparene and (−)-δ-cuparenol, two cuparane-type sesquiterpenoids, were synthesized from β-cyclogeraniol in 47% and 27% overall yield, respectively, using a Katsuki−Sharpless asymmetric epoxidat...

The synthesis of 4,7-di- and 4,7,7-trisubstituted 3,6-dioxoperhydropyrrolo[1,2- a ]pyrazine-7-carboxylale derivatives is described. The approach used for the preparation of this heterocyclic template is based on the reductive animation of 4-ketodiesters derived from dipeptides.

Highly constrained 2-amino-3-oxohexahydroindolizino[8-7- b ]indole-5-carboxylate derivatives of general formula 1 have been developed as novel β-turn mimetics. Molecular dynamics studies on model structures 2a and 2b have revealed that both indolizinoindole derivatives are able to adopt conformations close to those of ideal type II' β-tum. The asymmetric synthesis of this heterocyclic system was accomplished from 1,3-di- and 1,2,3-trisubstituted tetrahydro-β-carbolines, which were prepared in stereoselective or stereospecific way by application of the Pictet-Spengler reaction.

In order to enforce different spatial orientations in the C-terminal hexapeptide of neurotensin (NT8−13) and to gain information about the importance of the 10–11 peptide bond for binding to NT receptors, the Pro10-Tyr11 fragment has been replaced with (2R,8S,8aR)-, (2S,8S,8aR)-, (2S,8S,8aS)-, (2S,8R,8aS)- and (2R,8R,8aS)-8-amino-2-benzyl-3-oxoindolizidine-2-carboxylic acid. Molecular dynamics calculations and energy minimization studies have shown that, contrarily to the Pro-Tyr moiety, none of these indolizidines display a tendency to adopt type I and III β-turns, but those having (8S,8aR) or (8R,8aS) stereochemistry essentially adopt extended conformations and the (8S,8aS) stereoisomer prefers a nonstandard folding. The four diastereomeric NT8−13 analogues incorporating (8S,8aR) or (8R,8aS) indolizidines displayed binding affinities for the brain NT receptor similar to that of [Ala11]-NT8−13 and only five- to ninefold lower than that of the corresponding analogue, [Phe11]NT8−13. Although this slight decrease could be attributed to differences in conformational behavior between these constrained NT8−13 analogues and [Phe11]NT8−13 or NT8−13, it is not clear whether the β-turn around Pro10-AA11 (AA=Phe, Tyr) is conserved upon receptor binding. An excessive restriction in the motions of the aromatic side chain, imposed by the highly steric constraint of the indolizidine moiety, emerges as an alternative explanation. The findings reported here demonstrate the possibility of replacing the Pro10-Tyr11 dipeptide in NT8−13 with a non-peptide residue without affecting considerably the affinity for brain NT receptors.

The reaction sequence that converts Boc-L- or Boc-D-Orn(Z)-OH into 8-amino-3-oxoindolizidine-2-carboxylate derivatives has been examined, in order to determine the step during which partial racemization occurs. By using chiral derivatizating agents, it has been demonstrated that the temperature-dependent racemization takes place during the intramolecular reductive amination process, involved in the elaboration of the indolizidine ring by hydrogenation of the corresponding 4-keto diester derived from ornithine. It was shown from deuterium labelling experiments that this process proceeds through an equilibrium between imine–enamine intermediates which also accounts for the high stereoselectivity in the generation of the C-8a centre of the indolizidine skeleton.

A simple method for the synthesis of an azepane quaternary amino acid in enantiopure form is described. Theoretical, NMR, and X-ray studies indicated that this azepane-derived amino acid is an effective stabilizer of 3 10 helical structures in short peptides.

The deficit of 25-hydroxyvitamin D (25OHD) associated with secondary hyperparathyroidism (SHPT) is a frequent finding in chronic kidney disease (CKD) patients on haemodialysis (HD). These events are associated with increased morbidity and mortality rates of cardiovascular (CV) origin. Adequate 25OHD serum levels as well as the use of selective vitamin D receptor activators (VDRA) have been shown to have beneficial and independent effects on bone mineral metabolism and cardiovascular risk. Currently, there is still controversy regarding the type of supplementation needed by CKD patients on HD.The aim of our study was to evaluate whether there is a benefit of combination therapy with 25OHD, calcifediol and a VDRA, oral paricalcitol, on bone-mineral metabolism and inflammatory markers, compared to single treatment with each of these in a group of patients on HD.We performed a prospective study of 6 months, involving 26 patients in our HD unit. We randomised patients into two groups: group 1 (G1) received oral paricalcitol treatment at doses of 1 mcg/day. Group 2 (G2) was treated with 1 ampoule calcifediol/wk (0.266 mg/wk=16 000U) orally. After 3 months of treatment, calcifediol and paricalcitol were added to the G1 and G2 respectively at the same doses, keeping these treatments together for 3 months to complete the 6 months of follow-up. Laboratory tests were performed at months 0, 3 and 6, measuring in all patients serum markers of 25OHD, calcium (Ca), phosphorus (P) and PTH. Bone turnover markers measured were: alkaline phosphatase (AP), aminoterminal propeptide of procollagen type 1 (Pinp1) and carboxyl-terminal telopeptide of type I collagen (CrossLaps), and inflammatory markers: IL-8. We also collected data on levels of insulin, glucose, haemoglobin, erythropoiesis-stimulating agents (ESAs) and rates of resistance to EPO and HOMA (homeostasis model assessment).We detected a deficit of 25-hydroxyvitamin D in all patients studied, with a mean of 13.67 ± 4.81 ng/ml. Supplementation with oral calcifediol significantly corrects this deficit without evidence of toxicity (35.36 ± 33.68 ng/ml in G1 at 6 months and 59.21 ± 26.50 ng/ml in G2 at 3 months). Paricalcitol treatment significantly reduces PTH levels in G1 at 3 months (P.039). We also noted a decrease in bone marker Pinp1 with paricalcitol, pointing to a possible direct effect on bone cells (P.001). Both treatment with paricalcitol and with calcifediol produced a significant decrease in levels of IL-8 (P.001), a known inflammatory marker, drawing attention to a trend towards better response to erythropoiesis-stimulating agents (ESAs), possibly related to the decrease in inflammation. The HOMA index did not change significantly.Based on our results, we cannot conclude that the association of calcifediol and paricalcitol produces advantages over the effect of each drug separately. In addition, Paricalcitol by itself appears to have a direct effect on cellular bone remodelling.

9 páginas, ilustraciones y tablas estadísticas., A series of incubation and leaching experiments were performed to assess the feasibility of three industrial by-products (red gypsum (RG), sugar foam (SF) and ashes from the combustion of biomass (ACB)) to reduce the leachability of Cu, Pb, Zn and As in a sediment of São Domingos mine (Portugal). The changes in the element solid phase speciation were also evaluated by applying a sequential extraction procedure. All amendments significantly reduced the leachability of Zn and Cu, whereas the treatment with RG + SF + ACB also decreased the mobility of As. The reduction in Cu leachability was especially remarkable. This could be due to the great affinity of carbonates (included in SF and SF + ACB amendments) to precipitate with Cu, and maghemite and rutile (RG amendment) for acting as relevant sorbents for Cu. Pb was the least mobile element in the sediment and none of the treatments reduced its mobility. The sequential extraction reveals that the amendments induced a significant decrease in the concentration of elements associated with the residual fraction. Cu, Pb and As are redistributed from the residual fraction to the Al, Fe, and Mn hydr(oxides) fraction and Zn from the residual fraction to the water/acid soluble, exchangeable and bound to carbonates pool., AGL2005-07017-C03-03. MPRJ

The chemical pretreatment with ozone of rye and wheat straws was carried out in a fixed bed reactor. The effect of ozone pretreatment time on lignin removal was determined. Glucose and xylose concentrations in the hydrolysates were also measured after the subsequent enzymatic hydrolysis step. Acid insoluble lignin reacts with ozone within the first 90 min reaction. Insoluble lignin reduction was about 50%. The higher hydrolysis yields were obtained after 120 min ozonation: the glucose yield ranged from 40% to 50% for rye straw and from 34% to 39% for wheat straw, whereas xylose yields were about 30%, independently of the cereal straw. The glucose yields corresponding to the untreated raw straws were considerably lower, about 10%. Longer ozonation time sharply reduced the production of monosaccharides, probably due to the formation of side products. The kinetic model, with the reaction parameters estimated, predicted reasonably well the experimental data.

The in vitro cytotoxicity assays of several enantiopure (3S,4S)- and (3R,4R)-1,3,4,4-tetrasubstituted β-lactams derived from amino acids have shown that the (3S,4S)-4-benzyl-1-p-methoxybenzyl-3-methyl-4-methoxycarbonyl derivative 2a, obtained from Phe, displays significant activity, which is comparable to that of the anticancer drug Doxorubicin against HT29 cell lines. Modifications at positions 1 and 4 of the β-lactam ring led to identify the Tyr(2,6-ClBz) analogu 26d with similar activity data to those of 2a. The synthesis and SAR of all these tetrasubstituted β-lactams are reported here.

The aim of this study was to identify the genetic defect in two patients having cardiac dysfunction accompanied by neurological symptoms, and in one case MRI evidence of cortical and cerebellar atrophy with hyperintensities in the basal ganglia. Muscle biopsies from each patient revealed single and combined mitochondrial respiratory chain deficiency. The complete mtDNA sequencing of both patients revealed two transitions in the mitochondrial tRNA Val gene (MT-TV) (m.1628C>T in Patient 1, and m.1644G>A in Patient 2). The functional and molecular analyses reported here suggest that the MT-TV gene should be routinely considered in the diagnosis of mitochondrial cardiomyopathies. © 2011 Elsevier B.V. and Mitochondria Research Society., This work was supported by Grants PI060205 (to B.B.), PI070167 (to R.G.), and PI060547 (to M.A.M.) from the Instituto de Salud Carlos III (ISCIII), Ministry of Science and Innovation (MICIN); and GEN-0269/2006 from the Comunidad de Madrid (CM) (to M.A.M. and R.G.).

A discrete library of linear and hydantoin-containing dipeptide derivatives, based on the Lys-Trp(Nps) scaffold, was prepared by solid-phase synthesis. SAR studies indicated that potency for TRPV1 blockade and selectivity towards NMDA is mainly dictated by the side-chain length and the basic nature of α, ω-groups in the N-terminal residue. The 2-Nps moiety at position 2 of Trp indole ring is preferred over the 2-pyridine one.

To explore further the chemistry of amino acid-derived β-lactams, their conversion to α,α-heterocyclic quaternary amino acid derivatives is investigated. The latter derivatives, containing 2-oxoazepane as the α,α-substituent, are synthesized by a simple Pd-C-catalyzed hydrogenolysis of Orn(Z)-derived 2-azetidinones. The rearrangement from four- to seven-membered lactam ring is driven by the key intramolecular opening of the 1-Boc-β-lactam, initiated by 7-exotrig ring closure from the NH2 of the Orn side chain. The synthetic route is applied to the stereoselective preparation of enantiomerically pure 4-amino-3-methyl-2-oxoazepane-4-carboxylate derivatives, for which the structure and configuration is confirmed by X-ray diffraction. Molecular modeling and NMR experiments indicate that these quaternary amino acids are able to drive the adoption of β-turn secondary structures when incorporated in model dipeptide derivatives.

Various cyanomethyleneamino pseudodipeptides were easily prepared in high yield by the Lewis acid catalyzed addition of trimethylsilyl cyanide to unstable aldimine intermediates, obtained from the reaction of N-protected α-amino aldehydes with C-protected amino acids. The two possible (R)- and (S)-epimers at the peptide bond surrogate chiral center were obtained. In this thermodynamically controlled synthesis, the absolute configurations of the α-amino aldehyde and the amino acid proved to be the main factors determining its stereoselectivity. The new N-Boc- and N-Z-protected pseudodipeptides were deblocked under standard conditions. In spite of the lability of the new peptide bond surrogate ψ[CH(CN)NH] in basic medium, high yields of C-deprotected pseudodipeptides were obtained by controlling the saponification conditions of the methyl esters. The use of free α-amino acids in the modified Srecker synthesis reported here can be employed as an alternative for the synthesis of C-deprotected cyanomethyleneamino pseudopeptides. The N- or C-elongation of these pseudodipeptides via the DCC method led to the corresponding ψ[CH(CN)NH] pseudotripeptides in high yields

Graphical abstract, SAR studies on an azetidine-containing dipeptide prototype inhibitor of HCMV are described. Three series of structurally modified analogues, involving substitutions at the N- and C-terminus, and at the C-terminal side-chain were synthesized and evaluated for antiviral activity. Aliphatic or no substituents at the C-carboxamide group, an aliphatic C-terminal side-chain, as well as a benzyloxycarbonyl moiety at the N-terminus were absolute requirements for anti-HCMV activity. The conformational restriction induced by the 2-azetidine residue into the dipeptide derivatives, identified by 1H NMR as a γ-type reverse turn, seems to have influence on the activity of these molecules.

Conformationally constrained dipeptoid analogues containing the type II′ β-turn mimic (2 S ,5 S ,11b R )-2-amino-3-oxohexahydroindolizino[8,7- b ]indole-5-carboxylate framework in place of the α-MeTrp residue, show high binding affinity and selectivity for CCK-A receptors, suggesting that a turn-like conformation could contribute to the bioactive conformation at this CCK receptor subtype.

Replacement of the 2-Adoc- d -αMeTrp residue in the non-selective CCK 1 receptor agonist PD 170292 by the Z-(2 R ,5 R ,11b S )-IBTM skeleton, able to fix a type II β-turn-like conformation, led to a conformationally restricted dipeptoid analogue, namely 3a , which exhibited a notable increase in the CCK 1 selectivity and antagonist properties.

The first general approach toward the asymmetric synthesis of 4-alkyl-4-carboxy-2-azetidinones derived from amino acids is described. The stereoselective construction of the β-lactam ring was achieved through base-mediated intramolecular cyclization of the corresponding Nα-chloroacetyl derivatives bearing (+)- or (−)-10-(N,N-dicyclohexylsulfamoyl)isoborneol as chiral auxiliary (ee up to 82%).

Conveniently substituted 2-alkyl-2-carboxyazetidine amino acids have been incorporated into NGF and NT3 tetrapeptide sequences to investigate their utility as reverse turn inducers (γ- vs. β-turns). Despite the presence of an Asp residue at i position, highly preferred in β-turns, molecular modeling and NMR studies indicated that the azetidine-containing peptides mainly stabilized γ-turn conformations.

The synthesis of aminodeoxybestatin and epi-aminodeoxybestatin [(2S,3R)- and (2R,3R)-2,3-di-amino-4-phenylbutanoyl-L-leucine; (2S,3R)- and (2R,3R)-DAPBA-L-Leu)], bestatin and epi-bestatin analogues, respectively, in which the hydroxy group has been replaced with an amino group, is described by two different methods. The first one involves the synthesis of bis-(N-Z)-DAPBA, by homologation of N-Z-phenylalanine, via a modified Strecker synthesis followed by subsequent coupling with the methyl ester of L-leucine and removal of the protecting groups. Following this procedure, 25% racemization at the C-3 centre of the DAPBA derivatives took place during the homologation reaction. The second method involves the stereospecific SN2 nucleophilic substitution of the 2-hydroxy group of (2R,3R)- and (2S,3R)-3-(benzyloxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl-L-leucine methyl esters [(2R,3R)- and (2S,3R)-N-Z-AHPBA-L-Leu-OMe], and subsequent saponification, azido reduction and removal of the N-Z-protecting group. Replacement of the hydroxy group of bestatin and epi-bestatin with an amino group results in a decrease in their aminopeptidase (AP-B, AP-M and Leu-AP)-inhibitory potencies.

(2S,3R)-3,7-Diamino-2-hydroxy-heptanoyl-Leu-Pro-OH [(2S,3R)-DAHHA-Leu-Pro-OH, 4], analogue of the N-terminal tripeptide of probestin, has been synthesized, and tested as inhibitor of AP-B, Leu-AP, AP-M, and enkephalin-degrading APs, and as analgesic. In order to establish structure-activity relationships the dipeptide (2S,3R)-DAHHA-Pro-OH (5) and the tripeptide (2S, 3R)-DAHHA-Ala-Pro-OH (6) were also prepared. Compounds 4 and 6 were potent and selective inhibitors of enkephalin-degrading APs and showed a prolonged antinociceptive effect. Hemmung von Aminopeptidasen und analgetische Wirkung von (2S, 3R)-3,7-Diamino-2-hydroxy-heptansaure enthaltenden Tripeptidanaloga des N-terminalen Tripeptids von Probestin (2S,3R)-3,7-Diamino-2-hydroxy-heptanoyl-Leu-Pro-OH [(2S, 3R)-DAHHA-Leu-Pro-OH, 4], ein Analoges des N-terminalen Tripeptids von Probestin, wurde synthetisiert und sowohl als Hemmstoff von AP-B, Leu-AP, AP-M und von Enkephalin-abbauenden APs und auch als Analgetikum gepruft. Zur Untersuchung von Struktur-Aktivitat-Beziehungen wurden ebenfalls das Dipeptid (2S,3R)-DAHHA-Pro-OH (5) und das Tripeptid (2S,3R)-DAHHA-Ala-Pro-OH (6) hergestellt. Die Verbindungen 4 und 6 sind starke und selektive Hemmstoffe von Enkephalin-abbauenden APs und zeigen eine verlangerte antinociceptive Wirkung.

To select individuals whose morbid obesity can be attributed mainly to their individual genetic profile. After excluding patients with potential monogenic syndromes or diseases associated with obesity, we evaluated the association of the single nucleotide polymorphisms (SNPs) rs1861868 and rs9939609 of the fat-mass and obesity-associated FTO gene with an inherited predisposition to morbid obesity.We evaluated 270 patients with morbid obesity and onset before the age of 14 years and selected 194 due to their phenotypes and family history; 289 control individuals were included. The rs1861868 and rs9939609 variants, located in the FTO gene, were genotyped. Genotype and haplotype frequencies were compared between cases and controls.The A allele of rs9939609 was associated with severe obesity starting in childhood among the Spanish population. The rs1861868 G/rs9939609 A haplotype of the FTO gene was also significantly associated with severe obesity in our population, with an odds ratio of 3.03 (95% confidence interval, 1.74-5.27).Analysis of the genetic basis of obesity requires rigorous selection of cases. In this study, the association of the rs9939609 SNP with obesity widely described in distinct populations was confirmed among overweight Spanish children. Genotyping rs1861868 allowed us to identify the first risk haplotype in the FTO gene, which is located in the adjacent haplotype block containing rs9939609. In-depth study of the variability of the FTO gene is essential to define its deleterious capacity.

An easy and versatile general method for the preparation of the new peptide bond surrogate Ψ[CH(CN)NH], by the Lewis acid catalyzed reaction of N-protected α-amino aldehydes with a C-protected amino acid or peptide in the presence of TMSCN, is described.

A series of diastereoisomeric dipeptides, analogues of the analgesic compound H-Trp(Nps)-Lys-OMe, containing 3-amino-2-hydroxy-4-[2-(o- nitrophenylthio)indol-3-yl]butanoic acid [AH(Nps)IBA] and Lys or Leu has been synthesized. These compounds were tested as aminopeptidase-M and -B (AP-M and AP-B) inhibitors and as analgesics. The AH(Nps)IBA-Leu dipeptides, independently of their stereochemistry, were poor inhibitors of AP-M and AP-B, with IC 50-values in the 10-4 mol dm-3 range, while the AH(Nps)IBA-Lys derivatives were poor AP-B inhibitors, with IC 50-values also in the 10-4 mol dm-3 range, and did not inhibit AP-M up to 10-3. All the AH(Nps)IBA-Lys derivatives induced a significant dose-related analgesic activity at 1-5 μg per mouse, which was dependent on the stereochemistry, while no analgesia was observed with the corresponding Leu-containing analogues. There is no relationship between the antinociceptive effects and the AP-M inhibitory potencies of this series of compounds, indicating that the inhibition of enkephalin-degrading AP-M is not an important factor for the mode of action of this series of analgesic dipeptides.

Nucleoamino acids, wherein D- and L-penicillamine and D-and L-cysteine are attached to uridine or thymidine through a carboxylic ester linkage, have been synthesized and evaluated as antivirals and aminopeptidase B (AP-B) inhibitors. The coupling of the α-amino-β-mercapto acids, N,S-protected as N-formylthiazolidines, to 2′,3′-O-isopropylideneuridine, 3′-O-acetylthymidine, 5′-O-tritylthymidine, and thymidine was achieved via the mixed anhydride formed from N,N-bis-(2-oxooxazolidin-3-yl)phosphorodiamidic chloride and the corresponding protected amino acid in the presence of 4-(dimethylamino)pyridine. Treatment of the protected compounds with 1 mol dm–3-HCl in refluxing MeOH, under argon, afforded the corresponding deprotected nucleoamino acids free of racemization. Neither the compounds herein described nor D-penicillamine showed anti-HIV-1 activity in MT-4 cells or antiviral activity against some other viruses at concentrations below the cytotoxicity threshold. Penicillamine and cysteine monoesters were equipotent with the corresponding free amino acid in inhibiting AP-B with an IC50 in the 10–4 mol dm–3 range, while the bis-(α-amino-β-mercaptoacyl)thymidine derivatives were approximately twice as potent as the monoesters.

N-Deprotection of Z- and Boc-aminomethylene pseudodipeptide methyl esters yielded not only the expected linear deprotected compounds but also the 2-ketopiperazine cyclic analogues. The extent of lactamization was found to be dependent on the nature of the amino acid, the sequence order, and the deprotection conditions. Hydrogenation of Z-pseudodipeptides containing N-terminal basic amino acids in acidic media afforded linear compounds, while replacement of these basic residues by Leu gave mixtures of linear and cyclic pseudodipeptides. The reverse-sequence analogues, with Lys or Arg at the C-terminus, yielded the corresponding 2-ketopiperazines as the only reaction products. Opposite results were obtained for C-terminal Leu derivatives in which almost no cyclization occurred. Hydrogenation under neutral conditions gave mainly cyclic derivatives, while linear analogues were predominant after treatment of Boc-protected pseudodipeptides with trifluoroacetic acid or HCl.

Theoretical calculations on the transition states of the cyclization of 2S-chloropropionyl amino acid derivatives to the corresponding β-lactams have served to explain the high stereoselectivity of the reaction, and have been the driving force to extend the procedure to the preparation of a Gly-derived 1,3,4-trisubstituted 2-azetidinone in enantiopure form. © 2007 Elsevier Ltd. All rights reserved.

The rules and norms set out in the Maastrich Treaty and in the Stability and Growth Pact (SGP) have involved for the European Monetary Union (EMU) member states the implementation of an orthodox strategy of fiscal policy based on the correction of fiscal imbalances and cuts in the current sizes of public revenues and expenditures.

A series of constrained pentapeptide analogues of the fragment Aβ 31–35 has been prepared using solid phase synthesis protocols. The results of conformational studies and surface plasmon resonance (SPR) experiments seem to indicate that the affinity of these constrained analogues for immobilized Aβ 25–35 peptide could be related to their ability to adopt a Leu34N-Ile31O β-turn-like folded conformation.

This review mainly covers last five year literature on CCK1R agonists and antagonists. These CCK1R ligands have been found following the two usual and complementary strategies for drug discovery: rational design based on structure activity relationships on the CCK-7 and CCK-4 peptide sequences of the endogenous ligands and random screening of diverse compounds, followed by hit optimization. The first group includes: chimeric bifunctional opioid/CCK peptides, designed as opioid agonists with balanced CCK1R/CCK2R antagonist activity for the treatment of neuropathic pain, antagonist and agonist dipeptoids, and 1,3-dioxoperhydropyrido[1,2-c]pyrimidine- and anthranilic acid-based antagonists. Among the ligands derived from random screening, a few new 1,4-benzodiazepine-, 1,5-benzodiazepine-, and five member ring heterocycle-based CCK1R ligands have been reported. Finally, taking into account the importance of receptor mapping studies for ligand optimization and future precise de novo receptor structure-based design of new selective and more effective ligands, the most significant conclusions of these studies have also been reviewed.

The synthesis of new indole alkaloid analogues, containing a 1,2,4,5,1 Ob, 1 Oc-hexahydropyrrolo[ 1 ',2',3': 1,9a,9]imidazo-[1,2-a]indole skeleton, via highly stereoselective novel domino cyclative halogenation or prenylation reactions of tryptophan-derived α-amino nitriles, is described.

[reaction: see text] The base-promoted cyclization of optically pure N-(p-methoxybenzyl)-N-(2-chloro)propionyl amino acid derivatives resulted in a diastereo- and enantioselective approach to valuable 1,3,4,4-tetrasubstituted beta-lactams. The stereochemical outcome of the reaction is exclusively governed by the configuration of the N-(2-chloro)propionyl moiety.

The transient receptor potential vanilloid member 1 (TRPV1). an integrator of multiple pain-producing stimuli, is regarded nowadays as an important biological target for the discovery of novel analgesics. Here, we describe the first experimental evidence for the behavior of an old family of analgesic dipeptldes, namely Xaa-Trp(Nps) and Trp(Nps)-Xaa (Xaa=Lys, Arg) derivatives, as potent TRPV1 channel bolckers. We also report the synthesis and biological investigation of a series of new conformatidnally restricted Trp(Nps)-dipeptide derivatives with improved TRPV1/ NMDA selectivity. Compound 15b, Which incorporates an N-terminal 2S-azetidine-derived Arg residue, was the most selective compound in this series. Collectively, a new family of TRPV1 channel blockers emerged from our results, although further modifications are required to fine-tune the potency/selectivity/ toxicity balance.

The influence of several modifications on the GPE tripeptide structure upon the binding to GluRs and on their neuroprotective effects has been studied. The results indicated that the prevention of neuronal death showed by GPE and some analogues is not directly related to their affinity at glutamate receptors., This work has been supported by the Spanish Ministry of Education and Science (SAF 2003-07207-C02) and Comunidad de Madrid (GR/SAL/0850/2004), and UTE project FIMA. S.A.A.D.D. holds a predoctoral fellowship from the Ministry of Education for Associated Units to CSIC.