Functional design of glycan-conjugated molecules using a chemoenzymatic approach.

Carbohydrates play important and diverse roles in the fundamental processes of life. We have established a method for accurately and a large-scale synthesis of functional carbohydrates with diverse properties using a unique enzymatic method. Furthermore, various artificial glycan-conjugated molecules have been developed by adding these synthetic carbohydrates to macromolecules and to middle- and low-molecular-weight molecules with different properties. These glycan-conjugated molecules have biological activities comparable to or higher than those of natural compounds and present unique functions. In this review, several synthetic glycan-conjugated molecules are taken as examples to show design, synthesis, and function.

Bioactive Natural Spirolactone-Type 6,7-seco-ent-Kaurane Diterpenoids and Synthetic Derivatives.

Diterpenoids are widely distributed natural products and have caused considerable interest because of their unique skeletons and antibacterial and antitumor activities and so on. In light of recent discoveries, ent-kaurane diterpenoids, which exhibit a wide variety of biological activities, such as anticancer and anti-inflammatory activities, pose enormous potential to serve as a promising candidate for drug development. Among them, spirolactone-type 6,7-seco-ent-kaurane diterpenoids, with interesting molecular skeleton, complex oxidation patterns, and bond formation, exhibit attractive activities. Furthermore, spirolactone-type diterpenoids have many modifiable sites, which allows for linking to various substituents, suitable for further medicinal study. Hence, some structurally modified derivatives with improved cytotoxicity activities are also achieved. In this review, natural bioactive spirolactone-type diterpenoids and their synthetic derivatives were summarized.

OA-GL21, a novel bioactive peptide from Odorrana andersonii, accelerated the healing of skin wounds.

Nowadays, the number of chronic trauma cases caused by a variety of factors such as the world's population-ageing and chronic diseases is increasing steadily, and thus effective treatment for chronic wounds has become a severe clinical challenge, which also burdens the patient both physically and financially. Therefore, it is urgent to develop new drugs to accelerate the healing of wounds. Bioactive peptides, which are relatively low cost, easy to produce, store and transport, have become an excellent choice. In this research, we identified a novel peptide OA-GL21, with an amino acid sequence of 'GLLSGHYGRVVSTQSGHYGRG', from the skin secretions of Odorrana andersonii Our results showed that OA-GL21 exerted the ability to promote wound healing of human keratinocytes (HaCaT) and human fibroblasts in a dose- and time-denpendent manner. However, OA-GL21 had no significant effect on the proliferation of these two cells. Significantly, OA-GL21 showed obvious ability to promote wound healing in the full-thickness skin wound model in dose- and scar-free manners. Further studies showed that OA-GL21 had no direct antibacterial, hemolytic, and acute toxic activity; it had weak antioxidant activities but high stability. In conclusion, this research proved the promoting effects of OA-GL21 on cellular and animal wounds, and thus provided a new peptide template for the development of wound-repairing drugs.

Total synthesis and functional analysis of microbial signalling molecules.

Communication is essential for all domains of life. Bacteria use a plethora of small molecules to sense and orchestrate intra- and interspecies communication. Within this review, we will discuss different groups of signalling molecules, including autoinducers, virulence factors and morphogenic substances. On selected examples, we will shortly discuss their ecological roles and biosynthetic proposals. The major part of this review will focus on a systematic overview of the different synthetic methods applied towards the synthesis of signalling molecules and derivatives thereof. The described examples highlight the importance of organic synthetic method development and diversity-oriented total syntheses for structure verification, structure-function analysis and target identification.

[Preliminary study on substitution of Antelope Horn in Danqi Piantan capsule with artificial bezoar].

To study the protective effect of Danqi Piantan capsule ( DPC) and its antelope horn substitution (DPCAS) on the cerebral ischemia, in order to preliminary study the possibility of replacing antelope horn with artificial bezoar. In this study, the left middle cerebral artery occlusion (MCAO) was adopted. Totally 150 SD rats were randomly divided into 5 groups: the sham operation group, the model group, the Danqi Piantan capsule (DPC) group (0.246 g x kg(-1) x d(-1)), the Danqi Piantan capsule without antelope horn (DPCRA) group (0.246 g x kg(-1) x d(-1)), the Danqi Piantan capsule without antelope horn and with double artificial bezoar (DPCDB) group (0.246 g x kg(-1) x d(-1)). The MCAO model was prepared 1 h later after the administration on the 5th day. At 24 h after the operation, the inner canthus blood was collected to determine the serum superoxide dismutase (SOD) activity and the endothelin (ET) content. At 72 h after the operation, the cerebral infarct size and the cerebral index were determined by TTC-staining. The fluorescent quantitative PCR method was used to detect brain Bcl-2, Caspase-3, IL-1ß, P-selectin, E-selectin, ICAM-1 mRNA expressions. The mmunohistochemical method was used to detect ICAM-1, IL-1ß, TNF-α, IL-6 expressions in ischemic penumbra. According to the results, compared with the model group, DPCDB and DPC groups showed almost consistent results, indicating both of the two group can significantly improved cerebral infarction index and cerebral index (P < 0.05), increase the serum SOD activity (P < 0.05), decrease the serum ET level and Caspase-3 expression, IL-1ß, P-selectin, E-selectin, ICAM-1 mRNA expressions in brain tissues (P < 0.05) and expressions of ICAM-1, IL-1,6, TNF-α, IL-6 positive cells in ischemic penumbra (P < 0.05) and increase the Bcl-2 expression (P < 0.05). The DPCRA group showed much lower impacts on indexes than DPCDB and DPC groups. This suggests that DPCDB and DPC reveal similar efficacies and antelope horn in Danqi Piantan capsule can be substitutes by artificial bezoar.

Serological detection of Toxoplasma gondii, Leishmania infantum and Neospora caninum in cats from an area endemic for leishmaniasis in Brazil / Detecção sorológica de Toxoplasma gondii, Leishmania infantum e Neospora caninum em gatos de uma área endêmica para leishmaniose no Brasil

An investigation was made into the occurrence of antibodies to Toxoplasma gondii, Leishmania infantum and Neospora caninum in 151 domestic cats, based on the indirect fluorescent antibody test (IFAT). Serum samples were collected from 151 domestic cats (65 free-roaming and 86 domiciled cats; 55 males and 96 females) in Campo Grande, Mato Grosso do Sul, Brazil between January and April 2013. IgG antibodies to T. gondii, L. infantum and N. caninum were found, respectively, in 49 (32.5%), 34 (22.5%) and 10 (6.6%) sampled cats. A positive correlation was found between T. gondii and N. caninum, T. gondii and L. infantum, and N. caninum and L. infantum (p <0.05) infections. Also, a significant interaction was identified between gender and area of activity on the probability of T. gondii (p = 0.0324) infection. However, no significant interaction was observed between gender and area of activity on infections by either N. caninum or L. infantum. This study showed that cats from an area endemic for visceral leishmaniasis in Brazil are exposed to three different protozoans, two of which are causal agents of important zoonosis.

O presente estudo teve como objetivo investigar a ocorrência de anticorpos anti-Toxoplasma gondii, Leishmania infantum e Neospora caninum, em 151 gatos, por meio da Reação de Imunofluorescência Indireta (RIFI). Entre os meses de janeiro e abril de 2013, amostras de soro foram coletadas de 151 gatos domésticos (65 gatos errantes e 86 gatos domiciliados; 55 machos e 96 fêmeas), de Campo Grande, Mato Grosso do Sul, Brasil. Anticorpos IgG anti-T. gondii, anti-L. infantum e anti-N. caninum foram encontrados em 49 (32,5%), 34 (22,5%) e 10 (6,6%) gatos amostrados, respectivamente. Verificou-se uma associação estatisticamente significativa entre as infecções por T. gondii e N. caninum, T. gondii e L. infantum e N. caninum e Leishmania infantum (p <0,05). Além disso, foi observada uma interação significativa entre sexo, área de atividade na probabilidade de infecção por T. gondii (p = 0,0324). No entanto, não foi observada interação significativa entre sexo e área de atividade nas infecções por N. caninum e L. infantum. Este estudo mostrou que os gatos de uma área endêmica brasileira para leishmaniose visceral são expostos a três diferentes protozoários, sendo dois deles importantes agentes zoonóticos.

[Application of biosensors from the point of drug research]. / Bioszenzorok alkalmazhatósága a gyógyszerkutatás szemszögébol.

With the increasing number of protein active agents produced by the biotechnological route, the suitable analytical methods will also be important. The detection of small changes of protein and the monitoring of the processes of the biotechnological procedure are important. Biosensors can be applied for the detection of very low concentrations with nearly 100% selectivity. The aims of our work are to give basic information about biosensors, about their grouping and potential field of application.

Chemoenzymatic total synthesis of the phytotoxic geranylcyclohexentriol (-)-phomentrioloxin.

The enantiomeric form, 1R, of the structure (1S) assigned to the phytotoxic natural product phomentrioloxin has been synthesized in seven steps from the homochiral cis-1,2-dihydrocatechol 3. These studies reveal that the true structure of phomentrioloxin is represented by 1R and not by 1S.

An expedient protecting-group-free total synthesis of (±)-dievodiamine.

The first total synthesis of the Evodia rutaecarpa derived natural product dievodiamine is described. The convergent synthesis was performed without protecting groups, delivering a route that is short and high yielding and uses limited chromatography. Key steps include organometallic addition into a DHED adduct and the Stille coupling of two advanced intermediates to complete the synthesis.

Modulation of cellular senescence in fibroblasts and dermal papillae cells in vitro.

A hexapeptide (Hexapeptide-11) of structure Phe-Val-Ala-Pro-Phe-Pro (FVAPFP) originally isolated from yeast extracts and later synthesized by solid state synthesis to high purity has demonstrated an ability to influence the onset of senescence in intrinsically aged fibroblasts, extrinsically aged fibroblasts, and extrinsically aged dermal papillae cells in vitro. The mechanism of senescence control is believed to be related to the peptide's ability to reversibly downregulate ataxia telangiectasia mutated (ATM) and p53 protein expression. The importance of p53 as the gatekeeping protein for monitoring cellular DNA damage is strategic for maintaining cellular health. ATM activates p53 by direct phosphorylation, causing cells to move into senescence which effectively moves them out of reproductive processes. Technologies that can influence ATM and p53 expression may offer unique benefits for controlling cellular senescence and effectively delaying cellular aging processes. The influence on ATM and p53 expression is noted to occur in both cell lines at peptide concentrations between 0.1% and 1.0%. The implications of these effects for aging benefits for skin and hair is important as, to date, no known small peptide has been suggested to demonstrate this effect in such a reversible and dose-dependent fashion.

Synthesis of zinc-based nanomaterials: a biological perspective.

Nanoparticles are the materials characterised by dimensions of the order of 100 nm or less. They exhibit a high surface/volume ratio leading to different properties very different from those of the bulk materials. The development of uniform nanoparticles has been intensively pursued because of their technological and fundamental scientific importance. A number of chemical methods are available and are extensively used, but these are often energy intensive and use toxic chemicals. An alternative approach for the synthesis of uniform nanoparticles is the biological route that occurs at ambient temperature, pressure and at neutral pH. The main aim of this review is to enlist and compare various methods of synthesis of zinc-based nanoparticles with emphasis on the biological method.

Synthesis of arylnaphthalene lignan scaffold by gold-catalyzed intramolecular sequential electrophilic addition and benzannulation.

An intramolecular approach to generate compounds containing an arylnaphthalene lignan scaffold in high yields is presented. It involves a sequential intramolecular electrophilic attack of carbonyl on arylalkyne followed by benzannulation catalyzed by gold salt. AuCl(3) in combination with AgSbF(6) works better to effect this transformation. Selected products have been converted into arylnaphthalene lactone natural products such as justicidin E, taiwanin C, and retrojusticidin B.

Hippocampal and cortical neuronal growth mediated by the small molecule natural product clovanemagnolol.

The use of small molecule surrogates of growth factors that directly or indirectly promote growth represents an attractive approach to regenerative medicine. With synthetic access to clovanemagnolol, a small molecule initially isolated from the bark of the Bigleaf Magnolia tree, we have examined the small molecule's ability to promote growth of embryonic hippocampal and cortical neurons in serum-free medium. Comparisons with magnolol, a known promoter of growth, reveals that clovanmagnolol is a potent neurotrophic agent, promoting neuronal growth at concentrations of 10 nM. In addition, both clovanemagnolol and magnolol promote growth through a biphasic dose response.

Synthesis of antitrypanosomal 1,2-dioxane derivatives based on a natural product scaffold.

A short practical synthesis of a new natural product based scaffold (6), based on antitrypanosomal and antimalarial compounds isolated from different Plakortis species is described. The scaffold contains a peroxide unit that is surprisingly stable to chemical manipulation elsewhere in the molecule, enabling it to be elaborated into a small library of derivatives. It is stable to ozonolysis, reductive work-up with dimethylsulfide and the Wittig reaction with stabilized phosphorus ylides. The scaffold along with its Wittig analogues has displayed low to sub-micro molar (0.2-3.3 µM) antitrypanosomal activity.

Synthesis and biological properties of macrolactam analogs of the natural product macrolide (-)-A26771B.

Promising synthetic derivatives of macrolactone natural product (-)-A26771B have been designed and synthesized both from semisynthesis and total synthesis. Further optimization led to the first synthesis of macrolactam analogs of (-)-A26771B with improved antibacterial activity and metabolic stability.

Total synthesis of the natural product (±)-dibromophakellin and analogues.

(±)-Dibromophakellin has been synthesized in two steps from a known alkene intermediate. The key step in the synthesis is the NBS olefin activation to facilitate the addition of a guanidine molecule across the double bond.

Asymmetric [C + NC + CC] coupling entry to the naphthyridinomycin natural product family: formal total synthesis of cyanocycline A and bioxalomycin ß2.

A full account of our [C + NC + CC] coupling approach to the naphthyridinomycin family of natural products is presented, culminating in formal total syntheses of cyanocycline A and bioxalomycin ß2. The key complexity-building reaction in the synthesis involves the Ag(I)-catalyzed endo-selective [C + NC + CC] coupling of aldehyde 7, (S)-glycyl sultam 8, and methyl acrylate (9) to provide the highly functionalized pyrrolidine 6, which was carried forward to an advanced intermediate (compound 33) in Fukuyama's synthesis of cyanocycline A. Since cyanocycline A has been converted to bioxalomycin ß2, this constitutes a formal synthesis of the latter natural product as well. The multicomponent reaction-based strategy reduces the number of steps previously needed to assemble these complex molecular targets by one-third. This work highlights the utility of the asymmetric [C + NC + CC] coupling reaction in the context of a complex pyrrolidine-containing target and provides an illustrative guide for its application to other synthesis problems. The synthesis also fueled collaborative biological and biochemical research that identified a unique small molecule inhibitor of cell migration (compound 30).

Current status and future prospects of C1 domain ligands as drug candidates.

The second messenger diacylglycerol (DAG) plays a central role in the signal transduction of G-protein coupled receptors and receptor tyrosine kinases by binding to C1 domain of effector proteins. C1 domain was first identified in protein kinase C (PKC) which comprises a family of ten isoforms that play roles in diverse cellular processes such as proliferation, apoptosis and differentiation. Aberrant signaling through PKC isoforms and other C1 domain-containing proteins has been implicated in several pathological disorders. Drug discovery concerning C1 domains has exploited both natural products and rationally designed compounds. Currently, molecules from several classes of C1 domain-binding compounds are in clinical trials; however, still more have the potential to enter the drug development pipeline. This review gives a summary of the recent developments in C1 domain-binding compounds.

Free radical 5-exo-dig cyclization as the key step in the synthesis of bis-butyrolactone natural products: experimental and theoretical studies.

Radical cyclization reactions were performed by 5-exo-dig mode to yield cis-fused bicyclic systems, leading to the synthesis of bis-butyrolactone class of natural products. The study was aimed at understanding the impact of alkyl side chains of furanoside ring systems in L-ara configuration on the radical cyclization. It was amply demonstrated by experimental studies that the increase in the length of the alkyl side chain has an effect on the cyclization: while efficient cyclization reactions could be realized with methyl and ethyl side chains, the yields were significantly reduced in the case of n-pentyl side chain. Theoretical studies using DFT and (RO)MP2 methods were carried out to analyze the influence of the substitution pattern on the cyclization barriers.