Identification of a novel retinoid by small molecule screening with zebrafish embryos

Small molecules have played an important role in delineating molecular pathways involved in embryonic development and disease pathology. The need for novel small molecule modulators of biological processes has driven a number of targeted screens on large diverse libraries. However, due to the specific focus of such screens, the majority of the bioactive potential of these libraries remains unharnessed. In order to identify a higher proportion of compounds with interesting biological activities, we screened a diverse synthetic library for compounds that perturb the development of any of the multiple organs in zebrafish embryos. We identified small molecules that affect the development of a variety of structures such as heart, vasculature, brain, and body-axis. We utilized the previously known role of retinoic acid in anterior-posterior (A-P) patterning to identify the target of DTAB, a compound that caused A-P axis shortening in the zebrafish embryo. We show that DTAB is a retinoid with selective activity towards retinoic acid receptors gamma and beta. Thus, conducting zebrafish developmental screens using small molecules will not only enable the identification of compounds with diverse biological activities in a large chemical library but may also facilitate the identification of the target pathways of these biologically active molecules.     

Novel inhibitors of human histone deacetylases: Design,synthesis and bioactivity of 3-alkenoylcoumarines

Histone deacetylases (HDACs) are well-established, promising targets for anticancer therapy due to their critical role in cancer development. Accordingly, an increasing number of HDAC inhibitors displaying cytotoxic effects against cancer cells have been reported. Among them, a large panel of chemical structures was described including coumarin-containing molecules. In this study, we described synthesis and biological activity of new coumarin-based derivatives as HDAC inhibitors. Among eight derivatives, three compounds showed HDAC inhibitory activities and antitumor activities against leukemia cell lines without affecting the viability of peripheral blood mononuclear cells from healthy donors.     

Essential oils components as a new path to understand ion channel molecular pharmacology

The discovery and development of new drugs targeting voltage-gated ion channels are important for treating a variety of medical conditions and diseases. Ion channels are molecular nanostructures expressed ubiquitously throughout the whole body, and are involved in many basic physiological processes. Over the years, natural products have proven useful in the pharmacological assessment of ion channel structure and function, while also contributing to the identification of lead molecules for drug development. Essential oils are complex chemical mixtures isolated from plants which may possess a large spectrum of biological activities most of them of clinical interest. Among their bioactive constituents, terpenes are small to medium-sized components and belong to different chemical groups. Various reports have drawn our attention to the fact that terpenes are novel compounds targeting voltage-gated ion channels. The purpose of this review is to provide a focused discussion on the molecular interaction between monoterpenes and phenylpropenes with voltage-gated ion channels in different biological scenarios.     

膜分离技术在寡糖制备与分离中的应用*

寡糖是多糖经过降解后得到的小分子活性物质,具有抗氧化、抗肿瘤、抗病毒和免疫调节等多种生物活性,是功能食品开发领域研究的热点。目前,寡糖的分离和制备主要采用离子交换色谱、凝胶渗透色谱以及两者联用的方法,分离时间长、制备成本高,难以实现寡糖的规模化分离和制备。膜分离技术(membrane separation technology,MST)是一种利用膜的选择性渗透作用,实现两组分或者多组分分离的技术,具有操作简单、分离效果好、高效节能等优点,特别是能够直接放大应用于规模化的分离工程,因此在寡糖等小分子的分离和制备等方面具有巨大的应用潜力。系统总结了膜分离技术在寡糖分离与制备领域的最新进展,综述了用于分离和制备寡糖的膜分离技术分类、分离工艺及其应用现状,并对目前膜分离技术用于大规模分离和制备寡糖过程中面临的挑战进行了讨论。     

Microalgae as sources of pharmaceuticals and other biologically active compounds

In the last decade the screening of microalgae, especially the cyanobacteria (blue-green algae), for antibiotics and pharmacologically active compounds has received ever increasing interest. A large number of antibiotic compounds, many with novel structures, have been isolated and characterised. Similarly many cyanobacteria have been shown to produce antiviral and antineoplastic compounds. A range of pharmacological activities have also been observed with extracts of microalgae, however the active principles are as yet unknown in most cases. Several of the bioactive compounds may find application in human or veterinary medicine or in agriculture. Others should find application as research tools or as structural models for the development of new drugs. The microalgae are particularly attractive as natural sources of bioactive molecules since these algae have the potential to produce these compounds in culture which enables the production of structurally complex molecules which are difficult or impossible to produce by chemical synthesis.     

Enzymatic synthesis of antithrombin III-binding heparan sulfate pentasaccharide

Heparan sulfate (HS) proteoglycans are crucial to numerous biological processes and pathological conditions, but to date only a few HS structures have been synthesized and characterized with regard to structure-function relationships. Because HS proteoglycans are highly diverse in structure, there are substantial limitations on their synthesis by classical chemical means, and thus new methods to rapidly assemble bioactive HS structures are needed. Here we report the biosynthesis of bioactive HS oligosaccharides using an engineered set of cloned enzymes that mimics the Golgi apparatus in vitro. We rapidly and efficiently assembled the antithrombin III-binding pentasaccharide in just 6 steps, in contrast to the approximately 60 steps needed for its chemical synthesis, with an overall yield at least twofold greater and a completion time at least 100 times faster than for the chemical process.     

Metagenomics and industrial applications

Different industries have different motivations to probe the enormous resource that is uncultivated microbial diversity. Currently, there is a global political drive to promote white (industrial) biotechnology as a central feature of the sustainable economic future of modern industrialized societies. This requires the development of novel enzymes, processes, products and applications. Metagenomics promises to provide new molecules with diverse functions, but ultimately, expression systems are required for any new enzymes and bioactive molecules to become an economic success. This review highlights industrial efforts and achievements in metagenomics.     

Chemoenzymatic synthesis of classical and non-classical anticoagulant heparan sulfate polysaccharides

Heparan sulfate (HS) polysaccharides interact with numerous proteins at the cell surface and orchestrate many different biological functions. Though many functions of HS are well established, only a few specific structures can be attributed to HS functions. The extreme diversity of HS makes chemical synthesis of specific bioactive HS structures a cumbersome and tedious undertaking that requires laborious and careful functional group manipulations. Now that many of the enzymes involved in HS biosynthesis are characterized, we show in this study how one can rapidly and easily assemble bioactive HS structures with a set of cloned enzymes. We have demonstrated the feasibility of this new approach to rapidly assemble antithrombin III-binding classical and non-classical anticoagulant polysaccharide structures for the first time.     

Marine microorganisms as an untapped source of bioactive compounds

The search for novel biologically active molecules has extended to the screening of organisms associated with less explored environments. In this sense, Oceans, which cover nearly the 67% of the globe, are interesting ecosystems characterized by a high biodiversity that is worth being explored. As such, marine microorganisms are highly interesting as promising sources of new bioactive compounds of potential value to humans. Some of these microorganisms are able to survive in extreme marine environments and, as a result, they produce complex molecules with unique biological interesting properties for a wide variety of industrial and biotechnological applications. Thus, different marine microorganisms (fungi, myxomycetes, bacteria, and microalgae) producing compounds with antioxidant, antibacterial, apoptotic, antitumoral and antiviral activities have been already isolated. This review compiles and discusses the discovery of bioactive molecules from marine microorganisms reported from 2018 onwards. Moreover, it highlights the huge potential of marine microorganisms for obtaining highly valuable bioactive compounds.     

Pharmaceutically active secondary metabolites of marine actinobacteria

Marine actinobacteria are one of the most efficient groups of secondary metabolite producers and are very important from an industrial point of view. Many representatives of the order Actinomycetales are prolific producers of thousands of biologically active secondary metabolites. Actinobacteria from terrestrial sources have been studied and screened since the 1950s, for many important antibiotics, anticancer, antitumor and immunosuppressive agents. However, frequent rediscovery of the same compounds from the terrestrial actinobacteria has made them less attractive for screening programs in the recent years. At the same time, actinobacteria isolated from the marine environment have currently received considerable attention due to the structural diversity and unique biological activities of their secondary metabolites. They are efficient producers of new secondary metabolites that show a range of biological activities including antibacterial, antifungal, anticancer, antitumor, cytotoxic, cytostatic, anti-inflammatory, anti-parasitic, anti-malaria, antiviral, antioxidant, anti-angiogenesis, etc. In this review, an evaluation is made on the current status of research on marine actinobacteria yielding pharmaceutically active secondary metabolites. Bioactive compounds from marine actinobacteria possess distinct chemical structures that may form the basis for synthesis of new drugs that could be used to combat resistant pathogens. With the increasing advancement in science and technology, there would be a greater demand for new bioactive compounds synthesized by actinobacteria from various marine sources in future.     

Enzymatic synthesis of oligosaccharides and neoglycoconjugates

Oligosaccharides involved in glycoconjugates play important roles in a number of biological events. To elucidate the biological functions of oligosaccharides, sufficient quantities of structurally defined oligosaccharides, are of limited availability by traditional purification methods, are required. Hence, chemical and enzymatic syntheses of oligosaccharides are becoming increasingly important in glycobiology and glycotechnology. In addition, oligosaccharides often occur as glycoconjugates attached to proteins or lipids. Hence, the development of simple and effective methods for synthesizing neoglycoconjugates such as neoglycoprotein and neoglycolipids is essential for an understanding of the biological function of these molecules. Here we review the most recent developments in the enzymatic synthesis of oligosaccharides and neoglycoconjugates.     

Metagenomics: an inexhaustible access to nature's diversity

The chemical industry has an enormous need for innovation. To save resources, energy and time, currently more and more established chemical processes are being switched to biotechnological routes. This requires white biotechnology to discover and develop novel enzymes, biocatalysts and applications. Due to a limitation in the cultivability of microbes living in certain habitats, technologies have to be established which give access to the enormous resource of uncultivated microbial diversity. Metagenomics promises to provide new and diverse enzymes and biocatalysts as well as bioactive molecules and has the potential to make industrial biotechnology an economic, sustainable success.     

Sitting above the maze: recent model discoveries in molecular science

The 2013 Nobel Prize in Chemistry has convinced the world that how important the role that computational sciences play in chemical and materials sciences. In this review, computational methods and rational molecule design, including quantum mechanics and molecular mechanics methods, have been applied to study electronic structures and the interactions in a number of important applications at molecular level. The applications which include bioactive compounds, drug candidates and photoactive molecules at Swinburne University in the past several years are discussed. The research is in close collaboration with world class experimental groups from spectroscopy, organic and medicinal synthesis laboratories and most recently to γ-ray spectroscopy as well as other theory groups in the world. Ionisation spectra of biomolecules and bioactive compounds including amino acids, DNA bases, cyclic dipeptides, drug candidates, complexes and photoactive molecules are discussed. Most recent projects such as infrared spectral studies of ferrocene, rational design of organic dyes in solar cell applications, and recent development in γ-ray spectra of positron annihilation in molecules are highlighted.     

Metabolic oligosaccharide engineering: perspectives, applications, and future directions

Many adhesion and signaling molecules critical for development, as well as surface markers implicated in diseases ranging from cancer to influenza, contain oligosaccharides that modify their functions. Inside a cell, complex glycosylation pathways assemble these oligosaccharides and attach them to proteins and lipids as they traffic to the cell surface. Until recently, practical technologies to manipulate glycosylation have lagged unlike the molecular biologic and genetic methods available to intervene in nucleic acid and protein biochemistry; now, metabolic oligosaccharide engineering shows promise for manipulating glycosylation. In this methodology, exogenously-supplied non-natural sugars intercept biosynthetic pathways and exploit the remarkable ability of many of the enzymes involved in glycosylation to process metabolites with slightly altered chemical structures. To date, non-natural forms of sialic acid, GalNAc, GlcNAc, and fucose have been incorporated into glycoconjugates that appear on the cell surface; in addition O-GlcNAc protein modification involved in intracellular signaling has been tagged with modified forms of this sugar. Reactive functional groups, including ketones, azides, and thiols, have been incorporated into glycoconjugates and thereby provide chemical 'tags' that can be used for diverse purposes ranging from drug delivery to new modes of carbohydrate-based cell adhesion that can be used to control stem cell destiny. Finally, strategies for further engineering non-natural sugars to improve their pharmacological properties and provide complementary biological activities, such as addition of short chain fatty acids, are discussed in this article.     

The potential of click reactions for the synthesis of bioactive triterpenes

Click reactions between alkynes and azides using the privileged scaffold of triterpenes have been of interest for biological chemistry. Many publications deal with the synthesis of novel bioactive molecules; these conjugates have also been used for bioanalytical and diagnostic purposes. As a result, conjugates of better physicochemical properties were obtained; even compounds of improved solubility in water and physiological fluids were made through the introduction of a triazol residue. “Hybrid-structures“, i.e. molecules consisting of two independently bioactive subunits linked by a triazole residue were higher bioactive than their parent compounds but not as active as expected, and with a few exceptions the ultimate breakthrough has not yet been achieved. Only in the synthesis of compounds with anti-leishmanial activity some new and promising lead structures were found. As a consequence, triazole modified triterpenes seem to hold their greatest future prospect rather as diagnostic reagents and molecular probes than as drugs.     

Enzymatic production and biological activities of chitosan oligosaccharides (COS): A review

Many researchers have focused chitosan as a source of potential bioactive material during past few decades. However, chitosan has several drawbacks to be utilized in biological applications, including poor solubility under physiological conditions. Therefore, a new interest has recently been emerged on partially hydrolyzed chitosan, chitosan oligosaccharides (COS). During the resent past, several technological approaches have been taken to prepare COS and, enzymatic preparation methods captured a great interest due to safe and non-toxic concerns. With time, new improvements were introduced to enzymatic production and presently it has been developed to a continuous production process. Many of the biological activities reported for COS, such as antimicrobial, anticancer, antioxidant, and immunostimulant effects are depend on their physico-chemical properties. In this review, we have summarized different enzymatic preparation methods of COS and some of their reported biological activities.     

Biotransformation: a green and efficient way of antioxidant synthesis

Antioxidant compounds play a vital role in human physiology. They prevent the oxidation of biomolecules by scavenging free radicals produced during physiochemical processes and/or as a result of several pathological states. A balance between the reactive oxygen species (free radicals) and antioxidants is essential for proper physiological conditions. Excessive free radicals cause oxidative stress which can lead to several human diseases. Therefore, synthesis of the effective antioxidants is crucial in managing the oxidative stress. Biotransformation has evolved as an effective technique for the production of structurally diverse molecules with a wide range of biological activities. This methodology surpasses the conventional chemical synthesis due to the fact that enzymes, being specific in nature, catalyze reactions affording products with excellent regio- and stereoselectivities. Structural transformation of various classes of compounds such as alkaloids, steroids, flavonoids, and terpenes has been carried out through this technique. Several bioactive molecules, especially those having antioxidant potential have also been synthesized by using different biotransformation techniques and enzymes. Hydroxylated, glycosylated, and acylated derivatives of phenols, flavonoids, cinnamates, and other molecules have proven abilities as potential antioxidants. A critical review of the biotransformation of these compounds into potent antioxidant metabolites is presented here.     

Ricin antitoxins based on lyotropic mesophases containing galactose amphiphiles

Lyotropic mesophases of the inverse hexagonal or cubic type are nanostructured materials that result from the self-assembly of amphiphilic surfactant molecules in water. The extremely large area of the surfactant-water interface inherent within these structures makes them attractive media for sorbent or encapsulant systems. Here, we report on the development of a new class of polyvalent materials that are based on the incorporation of bioactive ligands within lyotropic mesophases. In particular, we have studied the potential for these materials to behave as polyvalent antitoxins by incorporating synthetic galactose amphiphiles, which mimic the natural cell surface ligand for the protein toxin ricin. The study demonstrates that cubic morphology lyotropic mesophases containing galactose amphiphiles exhibit high specificity ricin uptake, with favorably high dissociation constants and high capacities. We suggest that lyotropic mesophase polyvalent ligands are thus promising materials for the incorporation of a broad range of cell surface recognition moieties and hence may have wide applicability as materials capable of partaking in biological recognition processes.     

An efficient and convenient microwave-assisted chemical synthesis of (thio)xanthones with additional in vitro and in silico characterization

Xanthones and their thio-derivatives are a class of pleiotropic compounds with various reported pharmacological and biological activities. Although these activities are mainly determined in laboratory conditions, the class itself has a great potential to be utilized as promising chemical scaffold for the synthesis of new drug candidates. One of the main obstacles in utilization of these compounds was related to the difficulties in their chemical synthesis. Most of the known methods require two steps, and are limited to specific reagents not applicable to a large number of starting materials. In this paper a new and improved method for chemical synthesis of xanthones is presented. By applying a new procedure, we have successfully obtained these compounds with the desired regioselectivity in a shorter reaction time (50s) and with better yield (>80%). Finally, the preliminary in vitro screenings on different bacterial species and cytotoxicity assessment, as well as in silico activity evaluation were performed. The obtained results confirm potential pharmacological use of this class of molecules.     

Chemoenzymatic synthesis of oligosaccharides and glycoproteins

Oligosaccharides are involved in a wide range of biological processes including, for example, bacterial and viral infection, cancer metastasis, the blood-clotting cascade and many other crucial intercellular recognition events. The molecular details of these biological recognition events are, however, not well understood. To express their function, oligosaccharides often occur as glycoconjugates attached to proteins (called glycoproteins) or lipids (called glycolipids) that are often found on the surface of cells. Such physiological relevance has stimulated researchers to make significant advances in oligosaccharide and glycoprotein preparation despite the chemically imposing and polydisperse nature of these molecules. The chemical and Chemoenzymatic methods developed recently have facilitated the synthesis of structurally defined oligosaccharides and glycoconjugates such that a more thorough understanding of their biological function and potential therapeutic application can be addressed.