A new multi-gram synthetic route to labeling precursors for the D(2/3) PET agent 18F-fallypride

This Letter describes a new multi-gram synthetic protocol for the preparation of the classic tosylate labeling precursor for the D(2/3) PET agent [(18)F]fallypride. In the course of our studies, we also discovered two novel labeling precusors, the previously undescribed mesylate and chloro congeners of fallypride.     

Noni as an anxiolytic and sedative: A mechanism involving its gamma-aminobutyric acidergic effects

Noni (Morinda citrifolia) is increasing in worldwide popularity as a food or dietary supplement with versatile health benefits. The aim of this study was to investigate the effects of Noni fruit on anxiety symptoms in vitro. To this end, a competitive GABAa receptor-binding assay was developed. Our preliminary study indicates that the methanol crude extract of Noni fruit showed significant affinity to the gamma-aminobutyric acid A (GABAa) inhibitory neurotransmitter receptors, and displayed 75% binding inhibition of the agonist radioligand [3H] muscimol at a concentration of 100 microg/ml. Further experiments demonstrated that the MeOH extract, and its BuOH and H2O partitions, exhibited IC50 values of 22.8, 27.2, and 17.1 microg/ml, respectively, in the GABAa-binding assay. Experimental results with Noni fruit indicate the presence of competitive ligand(s), which may bind to the GABAa receptor as an agonist, and thus induce its anxiolytic and sedative effects. The study provides an in vitro rationale for one of Noni's versatile and traditional uses. In addition, an HPLC fingerprint profile of the methanolic extract of Noni fruit has been established for quality control purpose.     

A new synthetic route to thioacetyl-functionalised 2,2′-bipyridyl complexes

A fast two-step synthetic approach for 4,4′-thioacetyl-functionalised 2,2′-bipyridine is described. Ethylcarbamoyl groups are used as spacers between the sulfur atoms and the pyridyl rings. Both reactions proceed in a highly selective manner. The coordinating properties of the ligand have been assessed.     

A new synthetic route to 2- and 4-methoxyestradiols by nucleophilic substitution

A new snythetic route to 2- and 4-methoxyestradiols is described. Benzo-15-crown-5 with CuI catalyzes the specific nucleophilic substitution at the carbon atom carrying a non-activated halogen on ring A of the estradiol.     

A new synthetic route to 2-hydroxyl steroidal estrogens via acetylation and dakin oxidation

This paper describes a new two-step synthetic route to 2-hydroxy estrogens from either estrone or estradiol, via 2-acetylation followed by Dakin oxidation. This approach is characterized by its simplicity and excellence of yield.     

CL 218,872 Binding to Benzodiazepine Receptors in Rat Spinal Cord: Modulation by γ-Aminobutyric Acid and Evidence for Receptor Heterogeneity

The binding of the triazolopyridazine CL 218,872 to central benzodiazepine receptors identified with [3H]Ro 15-1788 was studied in extensively washed homogenates of rat spinal cord and cerebral cortex. CL 218,872 displacement curves were shallow in both spinal cord (nH = 0.67) and cortex (nH = 0.54), suggesting the presence of type 1 and type 2 benzodiazepine receptors in both tissues. CL 218,872 had lower affinity in spinal cord (IC50 = 825 nM) than cortex (IC50 = 152 nM), possibly reflecting the presence of fewer type 1 sites in the cord. Activating gamma-aminobutyric acid (GABA) receptors with 10 microM muscimol resulted in a two- to threefold increase in CL 218,872 affinity in both tissues without changes in the displacement curve slope. This indicates that GABA enhances CL 218,872 affinity for both type 1 and type 2 sites in both spinal cord and cerebral cortex.     

A simple and convenient synthetic route to Ulipristal acetate

We set out to describe a new and efficient route for preparing Ulipristal acetate with a good yield. The selected epoxidization conditions gave out 80% of 5α,10α-epoxide 2a in the two diastereoisomers which greatly improved the yield of 11β-substituted isomer 4a. And phenyl–sulfinyl compound 6 was synthesized from ketone 5 directly treated with phenylsulfenyl chloride in the presence of triethylamine. These synthetic procedures is only 8 steps, less than currently reported in the literature, but more suitable for industrial process.     

A new naphthalene derivative with anti-amyloidogenic activity as potential therapeutic agent for Alzheimer's disease

The aggregation of β-amyloid peptides is associated to neurodegeneration in Alzheimer’s disease (AD) patients. Consequently, the inhibition of both oligomerization and fibrillation of β-amyloid peptides is considered a plausible therapeutic approach for AD. Herein, the synthesis of new naphthalene derivatives and their evaluation as anti-β-amyloidogenic agents are presented. Molecular dynamic simulations predicted the formation of thermodynamically stable complexes between the compounds, the Aβ_1-42 peptide and fibrils. In human microglia cells, these compounds inhibited the aggregation of Aβ_1-42 peptide. The lead compound 8 showed a high affinity to amyloid plaques in mice brain ex vivo assays and an adequate log P_oct/PBS value. Compound 8 also improved the cognitive function and decreased hippocampal β-amyloid burden in the brain of 3xTg-AD female mice. Altogether, our results suggest that 8 could be a novel therapeutic agent for AD.     

A new synthetic method for 99mTc labeled N-Pyridoxyl-5-methyltryptophan as a hepatoma imaging agent

N-Pyridoxyl-5-methyltryptophan (5-PMT) was synthetized by a simplified method using sodium borohydride for the reduction of a Schiff base of pyridoxal and 5-methyltryptophan. Lyophilized kits containing 5-PMT, stannous chloride and l-(+)-ascorbic acid were prepared and labeled to afford ^99mTc-5-PMT with 96% or higher radiochemical purity analysed by two thin-layer chromatographic solvent systems. ^99mTc-5-PMT showed a rapid blood clearance, a faster hepatobiliary transit and a lower renal retention in comparison with ^99mTc-5-EHIDA in rats. Eleven (61%) of 18 patients with histologically confirmed hepatocellular carcinoma showed positive images at 2 to 5 h after i.v. injection. The smallest tumor that could be identified was 2 cm in diameter with the best tumor/liver ratio of 4. In conclusion, ^99mTc-5-PMT synthesized by sodium borohydride reduction shows great promise as a useful hepatoma imaging agent.     

A new route for the synthesis of Streptococcus pneumoniae 19F and 19A capsular polysaccharide fragments avoiding the β-mannosamine glycosylation step

The recently described [Attolino, E.; Bonaccorsi, F.; Catelani, G.; D’Andrea, F. Carbohydr. Res. 2008, 343, 2545–2556.] β-d-MaNAcp-(1→4)-β-d-Glcp thiophenyl glycosyl donor 3 was used in α-glycosylation reactions of OH-2 and OH-3 of the suitably protected p-MeO-benzyl α-l-rhamnopyranoside acceptors 7 and 8. Glycosylation of the axial OH-2 of 7 took place in high yield (76%) and with acceptable stereoselectivity (α/β = 3.4) leading to the protected trisaccharide α-11, corresponding to the repeating unit of Streptococcus pneumoniae 19F. The same reaction on equatorial OH-3 of acceptor 8 gave the trisaccharide α-15, a constituent of the repeating unit of S. pneumoniae 19A, but in lower yield (41%) and without stereoselection (α/β = 1:1.3). Utilizing the introduced orthogonal protection of OH-1 and OH-4″, the trisaccharide α-11 was transformed into a trisaccharide building block suitable for the synthesis of its phosphorylated oligomers.     

An efficient synthetic route for preparation of antimycobacterial wollamides and evaluation of their in vitro and in vivo efficacy

A convenient solid phase peptide synthetic (SPPS) route is reported for the preparation of antimycobacterial wollamides. The method is based on on-resin head-to-tail cyclization and is fast, efficient and amenable to automation. The in vitro antimycobacterial activities of the newly synthesized wollamides were evaluated against M. tuberculosis H37Rv (Mtb H37Rv). To assess their drug-likeness, in vitro pharmacokinetic (ADME) profiling was also performed. For wollamides with potent extracellular potency, intracellular activities and in vivo efficacy were determined. The results disclose the potent antimycobacterial (MIC_{Mtb H37Rv}?=?1.1?µM) and suitable drug-like properties of wollamide A (4b). Out of the synthesized wollamides, four compounds (4b–e) exhibited potent intracellular activities against Mtb H37Rv infected human macrophages (IC₅₀?=?0.2–1.3?µM). Results of in vivo blood exposure and efficacy assays for 4d and 4e are discussed.     

Allylation and propargylation of chiral cyanopropanoates: an efficient route to long chain alpha-substituted alpha-methyl alpha-amino acids

alpha-Methyllysine and 2-amino-2-methylundecanoic acid, two alpha,alpha-disubstituted unnatural glycines, were synthesized using highly diastereoselective allylation or propargylation of chiral (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyanopropanoate as the key step to introduce the long side chain. Chirality 16:106-111, 2004.     

A mobile agent model for fault-tolerant manipulation on distributed objects

In this paper, we discuss how to realize fault-tolerant applications on distributed objects. Servers supporting objects can be fault-tolerant by taking advantage of replication and checkpointing technologies. However, there is no discussion on how application programs being performed on clients are tolerant of clients faults. For example, servers might block in the two-phase commitment protocol due to the client fault. We newly discuss how to make application programs fault-tolerant by taking advantage of mobile agent technologies where a program can move from a computer to another computer in networks. An application program to be performed on a faulty computer can be performed on another operational computer by moving the program in the mobile agent model. In this paper, we discuss a transactional agent model where a reliable and efficient application for manipulating objects in multiple computers is realized in the mobile agent model. In the transactional agent model, only a small part of the application program named routing subagent moves around computers. A routing subagent autonomously finds a computer which to visit next. We discuss a hierarchical navigation map which computer should be visited price to another computer in a transactional agent. A routing subagent makes a decision on which computer visit for the hierarchical navigation map. Programs manipulating objects in a computer are loaded to the computer on arrival of the routing subagent in order to reduce the communication overhead. This part of the transactional agent is a manipulating subagent. The manipulation subagent still exists on the computer even after the routing subagent leaves the computer in order to hold objects until the commitment. We assume every computer may stop by fault while networks are reliable. There are kinds of faulty computers for a transactional agent; current, destination, and sibling computers where a transactional agent now exists, will move, and has visited, respectively. The types of faults are detected by neighbouring manipulation subagents by communicating with each other. If some of the manipulation subagents are faulty, the routing subagent has to be aborted. However, the routing subagent is still moving. We discuss how to efficiently deliver the abort message to the moving routing subagent. We evaluate the transactional agent model in terms of how long it takes to abort the routing subagent if some computer is faulty.

A generally synthetic route to semiconducting metal sulfide nanocrystals by using corresponding metal powder and cysteine as metallic and sulfuric sources, respectively

The economical and large-scale preparations of metallic sulfides nanocrystals (NCs) would determine their practical industrial application. In this contribution, a series of sulfides NCs such as ZnS, CdS, PbS, Cu_xS, MnS and Bi₂S₃, have been harvested by thermolysis of a single source metal cysteinate obtained conveniently from the reaction between metal powder and cysteine in aqueous environment and constant atmosphere in glassware. The characterizations including TEM, XRD, UV-Vis, FT-IR, TG-DSC, EDX and BET confirmed that the as-synthesized products are from the decomposition of metal cysteinate, of nanoscale in size, and of mesoporous materials. The generation, low cost and benign environment made this route technologically and scientifically interesting for the preparation of metallic sulfides NCs.     

A new anesthetic agent for use in the gerbil

Gerbils have been neglected in published reports on anesthesia. This study compared several dosages of Telazol used for anesthesia in the gerbil. Each group of animals injected with Telazol was evaluated for onset and duration of anesthesia and analgesia. Results showed Telazol to be a safe anesthetic and when dosed at 60 mg/kg to be suitable for major surgical procedures. Lower dosages of Telazol, in contrast, provided immobility and analgesia suitable for less nocioceptive and noninvasive experimental manipulations. Dosages of Telazol required for surgical depth of analgesia and anesthesia were accompanied by a prolonged recovery time. Gerbils should be monitored closely to insure a safe recovery when using the higher dosages.     

A new high-yield synthetic route to PET CB1 radioligands [11C]OMAR and its analogs

OMAR analogs reference standards and their corresponding desmethylated precursors were synthesized from substituted anilines either in 4 and 5 steps with 27-32% and 24-31% yield, or in 3 and 4 steps with 21-30% and 19-28% yield, respectively. [(11)C]OMAR and its analog radioligands were prepared from their desmethylated precursors with [(11)C]CH(3)OTf through O-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 50-65% radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB.     

A new bioproduction route for a novel antimicrobial peptide

Beta defensins are antimicrobial peptides (AMPs) with a broad spectrum antimicrobial behavior against pathogens while having minimal tendency to incur pathogen resistance. Human β-defensin 28 (hBD28) is a strongly cationic AMP and hence hypothesized to be highly effective in permeabilizing negatively-charged pathogen membranes. However, the scarcity of hBD28 in vivo has impeded detailed structure and antimicrobial studies of hBD28. Chemical synthesis of hBD28 rendered extremely poor yields due to inefficient cysteine oxidation. In this study, a rapid and scalable production route to produce bioactive hBD28 in Escherichia coli (E. coli) is reported. The design of a dual fusion tag expression construct was pivotal in enhancing soluble expression and easing purification of hBD28. The final hBD28 (purity >95%) displayed significant antimicrobial activity against E. coli K12 and showed dose-dependent killing kinetics. Circular dichroism spectroscopy confirmed the presence of both β-sheet and α-helix conformations in the secondary structure of hBD28.     

A new route to the evolution of cooperation

The Prisoner's Dilemma (PD) constitutes a widely used metaphor to investigate problems related to the evolution of cooperation. Whenever evolution takes place in well-mixed populations engaged in single rounds of the PD, cooperators cannot resist invasion by defectors, a feature, which is somewhat alleviated whenever populations are spatially distributed. In both cases the populations are characterized by a homogeneous pattern of connectivity, in which every individual is equivalent, sharing the same number of neighbours. Recently, compelling evidence has been accumulated on the strong heterogeneous nature of the network of contacts between individuals in populations. Here we describe the networks of contacts in terms of graphs and show that heterogeneity provides a new mechanism for cooperation to survive. Specifically, we show that cooperators are capable of exploring the heterogeneity of the population structure to become evolutionary competitive. As a result, cooperation becomes the dominating trait in scale-free networks of contacts in which the few highly connected individuals are directly inter-connected, in this way contributing to self-sustain cooperation.