Synthesis of α-aspartyl-containing cyclic peptides

Summary α-Aspartyl-containing cyclic pentapeptides were synthesised in high yields using a strategy that maintained fluorenylmethyl protection on the aspartic acid side chain during chain assembly, resin cleavage and cyclisation of the linear precursors. Tetra-n-butylammonium fluoride treatment of the fluorenylmethyl-protected cyclic peptides catalysed imide formation, whereas piperidine-induced deprotection resulted in good yields of the target cyclic peptides.     

Block‐cyclic redistribution over heterogeneous networks

Clusters of workstations and networked parallel computing systems are emerging as promising computational platforms for HPC applications. The processors in such systems are typically interconnected by a collection of heterogeneous networks such as Ethernet, ATM, and FDDI, among others. In this paper, we develop techniques to perform block-cyclic redistribution over P processors interconnected by such a collection of heterogeneous networks. We represent the communication scheduling problem using a timing diagram formalism. Here, each interprocessor communication event is represented by a rectangle whose height denotes the time to perform this event over the heterogeneous network. The communication scheduling problem is then one of appropriately positioning the rectangles so as to minimize the completion time of all the communication events. For the important case where the block size changes by a factor of K, we develop a heuristic algorithm whose completion time is at most twice the optimal. The running time of the heuristic is O(PK ²). Our heuristic algorithm is adaptive to variations in network performance, and derives schedules at run-time, based on current information about the available network bandwidth. Our experimental results show that our schedules always have communication times that are very close to optimal. This revised version was published online in July 2006 with corrections to the Cover Date.     

Do psychiatric diseases follow annual cyclic seasonality?

Seasonal affective disorder (SAD) famously follows annual cycles, with incidence elevation in the fall and spring. Should some version of cyclic annual pattern be expected from other psychiatric disorders? Would annual cycles be similar for distinct psychiatric conditions? This study probes these questions using 2 very large datasets describing the health histories of 150 million unique U.S. citizens and the entire Swedish population. We performed 2 types of analysis, using “uncorrected” and “corrected” observations. The former analysis focused on counts of daily patient visits associated with each disease. The latter analysis instead looked at the proportion of disease-specific visits within the total volume of visits for a time interval. In the uncorrected analysis, we found that psychiatric disorders’ annual patterns were remarkably similar across the studied diseases in both countries, with the magnitude of annual variation significantly higher in Sweden than in the United States for psychiatric, but not infectious diseases. In the corrected analysis, only 1 group of patients—11 to 20 years old—reproduced all regularities we observed for psychiatric disorders in the uncorrected analysis; the annual healthcare-seeking visit patterns associated with other age-groups changed drastically. Analogous analyses over infectious diseases were less divergent over these 2 types of computation. Comparing these 2 sets of results in the context of published psychiatric disorder seasonality studies, we tend to believe that our uncorrected results are more likely to capture the real trends, while the corrected results perhaps reflect mostly artifacts determined by dominantly fluctuating, health-seeking visits across a given year. However, the divergent results are ultimately inconclusive; thus, we present both sets of results unredacted, and, in the spirit of full disclosure, leave the verdict to the reader.

Should we expect psychiatric disorders to show a cyclic annual pattern? This study reveals that psychiatric diseases’ annual patterns were remarkably similar across the studied diseases in both the US and Sweden, with the magnitude of annual variation significantly higher in Sweden than in the US for psychiatric, but not infectious, diseases.     

Synthesis of cyclic RGD-peptides containing β-amino acids

Summary The solid phase synthesis of cyclic RGD-peptides containing β-amino acids according to two different protocols is described. The second strategy allows multiple or combinatorial syntheses of this type of cyclic peptides, because it enables backbone cyclization while the RGD-peptide is still bound to the resin. The newly synthesized RGD-peptides were characterized by MALDI-TOF MS and NMR and their physiological activity was determined by aggregometry.     

Cyanobactins—ribosomal cyclic peptides produced by cyanobacteria

Cyanobactins are small cyclic peptides that are produced by a diverse selection of cyanobacteria living in symbioses as well as terrestrial, marine, or freshwater environments. They include compounds with antimalarial, antitumor, and multidrug reversing activities and potential as pharmaceutical leads. Cyanobactins are produced through the proteolytic cleavage and cyclization of precursor peptides coupled with further posttranslational modifications such as heterocyclization, oxidation, or prenylation of amino acids. Cyanobactin gene clusters encode two proteases which cleave and cyclisize the precursor peptide as well as proteins participating in posttranslational modifications. The bioinformatic mining of cyanobacterial genomes has led to the discovery of novel cyanobactins. Heterologous expression of these gene clusters provided insights into the role of the genes participating in the biosynthesis of cyanobactins and facilitated the rational design of novel peptides. Enzymes participating in the biosynthesis of cyanobactins may prove useful as catalysts for producing novel cyclic peptides in the future. The recent discovery of the cyanobactin biosynthetic pathway in cyanobacteria extends our knowledge of their potential as producers of interesting metabolites.     

A new method for separating cyclic AMP from 5′-AMP with application to the assay for cyclic AMP phosphodiesterase

A new method for assay of cyclic AMP phosphodiesterase (EC 3.1.4.17) has been developed based on the observation that a mixture of cyclic AMP and AMP can be resolved on a column of florisil (activated magnesium silicate) at pH 7.0. The cyclic nucleotide is retained by the silicate and the AMP which is not adsorbed is virtually quantitatively recovered. The adsorption of cyclic AMP by florisil is greatly influenced by the pH of the buffer but independent of its ionic strength. In the actual assay cyclic[³H]AMP is incubated with the enzyme source in the presence of Mg²⁺ and the reaction is stopped by the addition of CCl₃COOH (0.3 m). The mixture is then neutralized by dilution with 10 vol of 0.5 m sodium phosphate buffer, pH 7.0, and applied on a small (0.4 × 4.0-cm) florisil column equilibrated with the same buffer. The column is eluted with 3 vol of the buffer and the radioactivity of the eluate which contains only [³H]AMP is measured. The use of cyclic[³H]AMP of high specific activity in the assay allows a high degree of sensitivity while the addition of CCl₃COOH instantaneously terminates the reaction allowing for increased precision. The assay compares favorably in simplicity and speed with those currently employed for cyclic AMP phosphodiesterase.     

α/β-Chimera peptide synthesis with cyclic β-sugar amino acids: the efficient coupling protocol

Amino Acids - The synthesis of α/β-chimeras comprises peptide bond formation from α- to β-, from β- to β-, and from β- to α-amino acid residues. The...     

Role of the nitric oxide/cyclic GMP/Ca2+ signaling pathway in the pyrogenic effect of interleukin-1β

Interleukin-1β (IL-1β) has a wide spectrum of inflammatory, metabolic, haemopoietic, and immunological properties. Because it produces fever when injected into animals and humans, it is considered an endogenous pyrogen. There is evidence to suggest that Ca²⁺ plays a critical role in the central mechanisms of thermoregulation, and in the intracellular signaling pathways controlling fever induced by IL-1β and other pyrogens. Data from different labs indicate that Ca²⁺ and Na⁺ determine the temperature set point in the posterior hypothalamus (PH) of various mammals and that changes in Ca²⁺ and PGE₂ concentrations in the cerebrospinal fluid (CSF) of these animals are associated with IL-1β-induced fever. Antipyretic drugs such as acetylsalicylic acid, dexamethasone, and lipocortin 5-(204–212) peptide counteract IL-1β-induced fever and abolish changes in Ca²⁺ and PGE₂ concentrations in CSF. In vitro studies have established that activation of the nitric oxide (NO)/cyclic GMP (cGMP) pathway is part of the signaling cascade transducing Ca²⁺ mobilization in response to IL-1β and that the ryanodine (RY)- and inositol-(1,4,5)-trisphosphate (IP₃)-sensitive pools are the main source of the mobilized Ca²⁺. It is concluded that the NO/cGMP/Ca²⁺ pathway is part of the signaling cascade subserving some of the multiple functions of IL-1β.     

Cytochrome b₅₅₉ and cyclic electron transfer within photosystem II

Cytochrome b??? (Cyt b???), β-carotene (Car), and chlorophyll (Chl) cofactors participate in the secondary electron-transfer pathways in photosystem II (PSII), which are believed to protect PSII from photodamage under conditions in which the primary electron-donation pathway leading to water oxidation is inhibited. Among these cofactors, Cyt b??? is preferentially photooxidized under conditions in which the primary electron-donation pathway is blocked. When Cyt b??? is preoxidized, the photooxidation of several of the 11 Car and 35 Chl molecules present per PSII is observed. In this review, the discovery of the secondary electron donors, their structures and electron-transfer properties, and progress in the characterization of the secondary electron-transfer pathways are discussed. This article is part of a Special Issue entitled: Photosystem II.     

Peptide nanotube composed of cyclic tetra-β-peptide having polydiacetylene

A cyclic tetra-β-peptide composed of three β-alanine residues and a L-β-homolysine residue having 10,12-pentacosadiynoic amide at the side chain was synthesized. The cyclic tetra-β-peptide formed peptide nanotubes in CDCl(3) . The diacetylene units along the peptide nanotubes were polymerized by UV irradiation to obtain peptide nanotubes with polydiacetylene along the nanotube. TEM and AFM observations of the polymerized cyclic tetra-β-peptides confirmed that the peptide nanotube structure was preserved after polymerization.     

Discovery of cyclic amine-substituted benzoic acids as PPARα agonists

A series of novel cyclic amine-substituted benzoic acid derivatives were synthesized and evaluated for their PPARα agonist activity. Strucure-activity relationship studies led to the identification of (S)-3-[3-[2-(4-chlorophenyl)-4-methylthyazole-5-carboxamido]piperidin-1-yl]benzoic acid (S)-4f (KRP-105) as a potent and high subtype-selective human PPARα agonist. (S)-4f showed excellent PK profile and oral administration of (S)-4f to high-fat diet dogs effectively lowered triglycerides.     

α-Carbonic anhydrases are sulfatases with cyclic diol monosulfate esters

Carbonic anhydrases (CA) catalyze activated ester hydrolysis in addition to the hydration of CO(2) to bicarbonate. They also show phosphatase activity with 4-nitrophenyl phosphate as substrate but not sulfatase with the corresponding sulfate. Here we prove that the enzyme is catalyzing the synthesis of cyclic diols from sulfate esters. 5-, 6- and 8-membered ring cyclic sulfates incorporating a neighboring secondary alcohol moiety were treated with CA II and yielded the corresponding cyclic diols. Inhibitory properties of obtained cyclic and original sulfate esters were then investigated on human carbonic anhydrase I (hCA I), hCA II, hCA IV and hCA VI (h?=?human isoform). K(I)-s of these compounds ranged between 32.7-423 μM against hCA I, 2.13-32.4 μM against hCA II, 13.7-234 μM against hCA IV and 76-278 μM against CA VI, respectively. The sulfatase activity of CA with such esters is amazing considering the fact that 4-nitrophenyl-sulfate is not a substrate of these enzymes.     

α-Carbonic anhydrases are sulfatases with cyclic diol monosulfate esters

Carbonic anhydrases (CA) catalyze activated ester hydrolysis in addition to the hydration of CO₂ to bicarbonate. They also show phosphatase activity with 4-nitrophenyl phosphate as substrate but not sulfatase with the corresponding sulfate. Here we prove that the enzyme is catalyzing the synthesis of cyclic diols from sulfate esters. 5-, 6- and 8-membered ring cyclic sulfates incorporating a neighboring secondary alcohol moiety were treated with CA II and yielded the corresponding cyclic diols. Inhibitory properties of obtained cyclic and original sulfate esters were then investigated on human carbonic anhydrase I (hCA I), hCA II, hCA IV and hCA VI (h?=?human isoform). K_I-s of these compounds ranged between 32.7–423 μM against hCA I, 2.13–32.4 μM against hCA II, 13.7–234 μM against hCA IV and 76–278 μM against CA VI, respectively. The sulfatase activity of CA with such esters is amazing considering the fact that 4-nitrophenyl-sulfate is not a substrate of these enzymes.     

CNGCs: prime targets of plant cyclic nucleotide signalling?

Cyclic nucleotide-gated channels (CNGCs) are a recently identified family of plant ion channels. They show a high degree of similarity to Shaker-type voltage-gated channels and contain a C-terminal cyclic nucleotide-binding domain with an overlapping calmodulin-binding domain. Heterologously expressed plant CNGCs show activation by cyclic nucleotides and permeability to monovalent and divalent cations. In plants, downstream effectors of cyclic nucleotide signals have so far remained obscure, and CNGCs might be their prime targets. The unique position of CNGCs as ligand-gated Ca(2+)-permeable channels suggests that they function at key sites where cyclic nucleotide and Ca(2+) signalling pathways interact. Such processes include plant defence responses, and two recently characterized Arabidopsis mutants in CNGC genes indeed show altered pathogen responses.     

Mutants of Serratia marcescens lacking cyclic nucleotide phosphodiesterase activity and requiring cyclic 3′,5′-AMP for the utilization of various carbohydrates

Adenine requiring mutants of Serratia marcescens SM-6-F'lac ⁺ have been found to grow well in minimal-glucose medium solely supplemented with cAMP. From one of these ade strains double mutants (called ade cpd) were isolated which could no longer utilize cAMP but which still grew on 5′AMP. Dialyzed cell extracts (soluble fraction) of the double mutants, assayed for cAMP phosphodiesterase, were unable to hydrolyze cAMP whereas cell extracts of the parental strains yielded 5′AMP at a rate of 1.6–2.0 μmoles min⁻¹ mg⁻¹ protein. The loss of the phosphodiesterase activity in S. marcescens cpd W1181 did not cause an accumulation of large amounts of cAMP as was found for the diesterase-negative mutant AB257^pc-1 of Escherichia coli. The induced synthesis of β-galactosidase in mutant cpd W 1181 showed about the same sensitivity to transient and permanent catabolite (glucose) repression as the corresponding cpd ⁺ strain. Starting from S. marcescens cpd W1181 three independent double mutants (called cpd cya) were isolated which required exogenous cAMP for utilizing various carbohydrates as carbon source, for motility and for the formation of extracellular lipase and the red pigment prodigiosine. The intracellular concentration of cAMP in these mutants, grown in nutrient broth, was 40–60% of that of the parental strain which is about 4×10⁻⁴ M. However, the adenylate cyclase in cell extracts of the mutants W1237 and W1270 was like that of the corresponding cya ⁺ strain (about 2×10⁻² μmoles min⁻¹ mg⁻¹ protein).     

Do the song pulses of Drosophila show cyclic fluctuations?

Following analysis of the song of two Drosophila species, Kyriacou and Hall in 1980 described a rhythmic variation in the intervals between sound pulses. This rhythmicity was species specific and various mutants also showed characteristic song-period rhythmicity. Recent attempts by Ewing and by Crossley to confirm the existence of the rhythms, using essentially similar methods, have failed; Kyriacou and Hall have since ascribed these failures to differences in technique and methods of measurement between them and their critics, and re-affirm that the rhythmicity they described exists. In view of the controversy surrounding the existence of song-period rhythmicity, a body of work on the genetics of this behaviour must be viewed with caution.     

Biotransformation of cyclic β-keto esters by Chlorella pyrenoidosa Chick

Algal transformations of three cyclic β-keto esters, methyl 2-oxocyclopentanecarboxylate (MCPC), ethyl 2-oxocyclohexanecarboxylate (ECHxC), and methyl 2-oxocycloheptanecarboxylate (MCHpC) were photoautotrophically studied with an axenic strain of Chlorella pyrenoidosa Chick. The three cyclic β-keto esters were transformed in two manners; reduction of the carbonyl group to a hydroxy group and elimination of the alkoxycarbonyl group. The former reaction occurred more often than the latter. The cis/trans ratios of the resulting alcohols in MCPC, ECHxC and MCHpC were 13 : 87, 15 : 85, and 65 : 35, respectively. The alkoxycarbonyl group elimination products were as follows: cyclopentanone and cyclopentanol in MCPC, cyclohexanone and cyclohexanol in ECHxC, and cycloheptanone in MCHpC.     

Neural adrenergic/cyclic AMP regulation of the immunoglobulin E receptor alpha-subunit expression in the mammalian pinealocyte: a neuroendocrine/immune response link?

The high affinity immunoglobulin E receptor (FcepsilonRI) complex is dedicated to immunoglobulin E-mediated allergic responses. Expression of the FcepsilonRI receptor is thought to be relatively stable and limited to mast cells, basophils, eosinophils, monocytes, Langerhans cells, platelets, and neutrophils. We now report that the FcepsilonRIalpha and FcepsilonRIgamma polypeptides are expressed in the pinealocyte, the melatonin-secreting cell of the pineal gland. Moreover, Fcer1a mRNA levels increased approximately 100-fold at night to levels that were higher than in other tissues examined. Pineal FcepsilonRIalpha protein also increased markedly at night from nearly undetectable daytime levels. Our studies indicate that pineal Fcer1a mRNA levels are controlled by a well described neural pathway that controls pineal function. This pathway includes the master circadian oscillator in the suprachiasmatic nucleus and passes through central and peripheral structures. The circadian expression of FcepsilonRIalpha in the pineal gland is driven by this neural circuit via an adrenergic/cyclic AMP mechanism. Pineal FcepsilonRIalpha and FcepsilonRIgamma may represent a previously unrealized molecular link between the neuroendocrine and immune systems.     

Influence of theophylline on concentrations of cyclic 3′,5′-adenosine monophosphate and cyclic 3′,5′-guanosine monophosphate of rat brain

The influence of theophylline (2.5–100 mg/kg p.o.) on cyclic 3,5-adenosine monophosphate (cAMP) and cyclic 3,5-guanosine monophosphate (cGMP) in brain of Sprague-Dawley rats (0.5–3.0 hr after administration of theophylline) was investigated. It was found that theophylline increases cAMP and cGMP levels when administered in a dose of 25 mg/kg or higher. A significant decrease of cGMP level was observed after administration of 10 mg/kg. The results of this study suggest that the influence of theophylline on cyclic nucleotide levels of rat brain is the result of two factors: (a) inhibitory properties of theophylline on cAMP and cGMP phosphodiesterases and (b) competition of theophylline with adenosine.