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.     

Physiological aspects. Part 1 in a series of papers devoted to surfactants in microbiology and biotechnology

Surfactants, both chemical and biological, are amphiphilic compounds which can reduce surface and interfacial tensions by accumulating at the interface of immiscible fluids and increase the solubility, mobility, bioavailability and subsequent biodegradation of hydrophobic or insoluble organic compounds. Investigations on their impacts on microbial activity have generally been limited in scope to the most common and best characterized surfactants. Recently a number of new biosurfactants have been described and accelerated advances in molecular and cellular biology are expected to expand our insights into the diversity of structures and applications of biosurfactants. Biosurfactants play an essential natural role in the swarming motility of microorganisms and participate in cellular physiological processes of signaling and differentiation as well as in biofilm formation. Biosurfactants also exhibit natural physiological roles in increasing bioavailability of hydrophobic molecules and can complex with heavy metals, and some also possess antimicrobial activity. Chemical- and indeed bio-surfactants may also be added exogenously to microbial systems to influence behaviour and/or activity, mimicking the latter effects of biosurfactants. They have been exploited in this way, for example as antimicrobial agents in disease control and to improve degradation of chemical contaminants. Chemical surfactants can interact with microbial proteins and can be manipulated to modify enzyme conformation in a manner that alters enzyme activity, stability and/or specificity. Both chemical- and bio-surfactants are potentially toxic to specific microbes and may be exploited as antimicrobial agents against plant, animal and human microbial pathogens. Because of the widespread use of chemical surfactants, their potential impacts on microbial communities in the environment are receiving considerable attention.     

Biological transformations of steroidal compounds: A review

Microbial transformation is an important tool for structural modification of organic compounds, especially natural products with complex structures like steroids. It can be used to synthesize chemical structures that are difficult to obtain by ordinary methods and as a model of mammalian metabolism due to similarity between mammalian and microbial enzyme systems. During recent years research has been focused on the structural modifications of bioactive steroids by using various microorganisms, in order to obtain biologically potent compounds with diverse structures. Steroidal compounds are responsible for important biological functions in the cells and manifest a variety of activities. This article covers the microbial transformation of sterols, steroidal hormones and some new types of steroids known as bufadienolides. Emphasis has placed on reporting metabolites that may be of general interest and on the practical aspects of work in the field of microbial transformations. The review covers the literature from 1994 to 2011.     

Fungal laccases as tools for the synthesis of new hybrid molecules and biomaterials

Laccase is a ligninolytic enzyme widely distributed in wood-rotting fungi and which is also found in a variety of molds and insects as well as some plants and bacteria. Its biological roles range from depolmerization of lignin, coal and humic acids via the oxidation of various mono- and diaromatic structures, to polymerization reactions and pigment formation in microbial cells or spores. Apart from its action in catabolic, depolymerizing and polymerizing processes, laccases have also been shown to be powerful enzymes for coupling two different molecules to create new low-molecular-weight products in high yield. In addition to their homomolecular coupling capabilities, laccases are also able to couple a hydroxylated aromatic substrate with a nonlaccase substrate of variable structure to create new heteromolecular hybrid molecules. Thus, laccases are increasingly finding applications in biotechnology in the fields of environment-friendly synthesis of fine chemicals and for the gentle derivatization of biologically active compounds e.g., antibiotics, amino acids, antioxidants, and cytostatics. Finally, oligomerization and polymerization reactions can lead to new homo- or heteropolymers and biomaterials. These may be useful in a wide range of applications including the production of polymers with antioxidative properties, the copolymerizing of lignin components with low-molecular mass compounds, the coating of cellulosic cotton fibers or wool, the coloring of hair and leathers, or the cross-linking and oligomerization of peptides.     

Peptides of arachnid venoms with insecticidal activity targeting sodium channels

Arachnids have a venom apparatus and secrete a complex chemical mixture of low molecular mass organic molecules, enzymes and polypeptide neurotoxins designed to paralyze or kill their prey. Most of these toxins are specific for membrane voltage-gated sodium channels, although some may also target calcium or potassium channels and other membrane receptors. Scorpions and spiders have provided the greatest number of the neurotoxins studied so far, for which, a good number of primary and 3D structures have been obtained. Structural features, comprising a folding that determines a similar spatial distribution of charged and hydrophobic side chains of specific amino acids, are strikingly common among the toxins from spider and scorpion venoms. Such similarities are, in turn, the key feature to target and bind these proteins to ionic channels. The search for new insecticidal compounds, as well as the study of their modes of action, constitutes a current approach to rationally design novel insecticides. This goal tends to be more relevant if the resistance to the conventional chemical products is considered. A promising alternative seems to be the biotechnological approach using toxin-expressing recombinant baculovirus. Spider and scorpion toxins having insecticidal activity are reviewed here considering their structures, toxicities and action mechanisms in sodium channels of excitable membranes.     

Anticancer agents suppressive for adult parasites of filariasis in Mongolian jirds

Eight chemical structures not previously reported to possess antifilarial activity have been identified. A total of 79 compounds with anticancer properties were evaluated for possible macrofilaricidal activity against Brugia pahangi and Acanthocheilonema viteae transplanted into male Mongolian jirds (Meriones unguiculatus). All eight active compounds were suppressive for the onchocerciasis type (Acanthocheilonema viteae) of the disease. None was macrofilaricidal for the lymphatic form (Brugia pahangi). These new structures may represent a nucleus around which effective drugs can be synthesized.     

Flavonoid compounds in maintenance of prostate health and prevention and treatment of cancer

Compounds based on a flavonoid (di-phenolic) ring structure are emerging as a potentially important new class of pharmaceutical compounds with a broad range of biological activities, most prominent of which are their potential role as anticancer agents. These compounds exert a wide range of upregulating and downregulating effects on signal transduction processes within cells in both plants and animals. The observation that human communities, which consume large quantities of these compounds (legume-based vegetarian diets), have a lower incidence of many degenerative diseases and some cancers has led to the speculation that these compounds, or synthetic analogs, may be of therapeutic value. This article reviews the evidence supporting this hypothesis and provides some examples of attempts to develop new therapeutics based on dietary isoflavones or novel isoflavonoid structures in maintaining prostate health and in cancer treatment and management. One of these compounds, phenoxodiol, is now in human clinical trials and has shown promise in patients with recurrent ovarian cancer where the cancer is refractory or resistant to standard chemotherapy, and in patients with hormone-refractory prostate cancer.     

Bioactive compounds produced by cyanobacteria

Cyanobacteria produce a large number of compounds with varying bioactivities. Prominent among these are toxins: hepatotoxins such as microcystins and nodularins and neurotoxins such as anatoxins and saxitoxins. Cytotoxicity to tumor cells has been demonstrated for other cyanobacterial products, including 9-deazaadenosine, dolastatin 13 and analogs. A number of compounds in cyanobacteria are inhibitors of proteases — micropeptins, cyanopeptolins, oscillapeptin, microviridin, aeruginosins- and other enzymes, while still other compounds have no recognized biological activities. In general cyclic peptides and depsipeptides are the most common structural types, but a wide variety of other types are also found: linear peptides, guanidines, phosphonates, purines and macrolides. The close similarity or identity in structures between cyanobacterial products and compounds isolated from sponges, tunicates and other marine invertebrates suggests the latter compounds may be derived from dietary or symbiotic blue-green algae.     

A New Set of Chemical Starting Points with Plasmodium falciparum Transmission-Blocking Potential for Antimalarial Drug Discovery

The discovery of new antimalarials with transmission blocking activity remains a key issue in efforts to control malaria and eventually eradicate the disease. Recently, high-throughput screening (HTS) assays have been successfully applied to Plasmodium falciparum asexual stages to screen millions of compounds, with the identification of thousands of new active molecules, some of which are already in clinical phases. The same approach has now been applied to identify compounds that are active against P. falciparum gametocytes, the parasite stage responsible for transmission. This study reports screening results for the Tres Cantos Antimalarial Set (TCAMS), of approximately 13,533 molecules, against P. falciparum stage V gametocytes. Secondary confirmation and cytotoxicity assays led to the identification of 98 selective molecules with dual activity against gametocytes and asexual stages. Hit compounds were chemically clustered and analyzed for appropriate physicochemical properties. The TCAMS chemical space around the prioritized hits was also studied. A selection of hit compounds was assessed ex vivo in the standard membrane feeding assay and demonstrated complete block in transmission. As a result of this effort, new chemical structures not connected to previously described antimalarials have been identified. This new set of compounds may serve as starting points for future drug discovery programs as well as tool compounds for identifying new modes of action involved in malaria transmission.     

Neue furanoeremophilane und andere sesquiterpene aus vertretern der gattung Euryops

Investigation of a further 27 Euryops species affords, besides known compounds, 55 new furanoeremophilanes together with several other compounds. The configuration of six furanoeremophilanes earlier given as 10β-H has to be changed to 10α-H. Furthermore 9 new eremophilenes were isolated; the configurations of four compounds of this type isolated before have had to be changed. One of the eremophilenes is esterified with 3-methylpent-3(E)-enoic acid, not found before in nature. Two hemiacetals, which are probable precursors of the furanoerephilanes, and a corresponding lactone are also present. Furthermore two benzylic esters, cis-caryophyllene, a bicyclo-germacrene derivative, and a new oplopanone derivative have been found. The structures are elucidated mainly by spectroscopic methods together with some chemical transformations. From the chemotaxonomic viewpoint, the high concentration of very variable furanoeremophilanes may be important. The proposed differentiation into sections however can not be clearly correlated with the chemical constituents, though some taxonomic conclusions seem to be supported by the chemical evidence.     

Lipid nanovesicles for biomedical applications: ‘What is in a name’?

Vesicles, generally defined as self-assembled structures formed by single or multiple concentric bilayers that surround an aqueous core, have been widely used for biomedical applications. They can either occur naturally (e.g. exosomes) or be produced artificially and range from the micrometric scale to the nanoscale. One the most well-known vesicle is the liposome, largely employed as a drug delivery nanocarrier. Liposomes have been modified along the years to improve physicochemical and biological features, resulting in long-circulating, ligand-targeted and stimuli-responsive liposomes, among others. In this process, new nomenclatures were reported in an extensive literature. In many instances, the new names suggest the emergence of a new nanocarrier, which have caused confusion as to whether the vesicles are indeed new entities or could simply be considered modified liposomes. Herein, we discussed the extensive nomenclature of vesicles based on the suffix “some” that are employed for drug delivery and composed of various types and proportions of lipids and others amphiphilic compounds. New names have most often been selected based on changes of vesicle lipid composition, but the payload, structural complexity (e.g. multicompartment) and new/improved proprieties (e.g. elasticity) have also inspired new vesicle names. Based on this discussion, we suggested a rational classification for vesicles.     

Synthesis and evaluation of new carbonic anhydrase inhibitors

A series of new sulfamide derivatives have been synthesized, their structures were confirmed by (1)H NMR and ESI-MS. Some target compounds were assessed by the tool of Dock6, and inhibition effects of all the new compounds on carbonic anhydrase II have been investigated. In addition, some compounds have been investigated for their antihypoxic effects in mice. Results indicated that nine target compounds exhibit as effectively as acetazolamide and 10 compounds have more potent inhibition effects on carbonic anhydrase II than acetazolamide. Three of them (I-8, I-18 and I'-3) can prolong markedly the survival time of mice in hypoxia, which are worth carrying out further studies.     

Synthetic antimicrobial peptides as agricultural pesticides for plant-disease control

There is a need of antimicrobial compounds in agriculture for plant-disease control, with low toxicity and reduced negative environmental impact. Antimicrobial peptides are produced by living organisms and offer strong possibilities in agriculture because new compounds can be developed based on natural structures with improved properties of activity, specificity, biodegradability, and toxicity. Design of new molecules has been achieved using combinatorial-chemistry procedures coupled to high-throughput screening systems and data processing with design-of-experiments (DOE) methodology to obtain QSAR equation models and optimized compounds. Upon selection of best candidates with low cytotoxicity and moderate stability to protease digestion, anti-infective activity has been evaluated in plant-pathogen model systems. Suitable compounds have been submitted to acute toxicity testing in higher organisms and exhibited a low toxicity profile in a mouse model. Large-scale production can be achieved by solution organic or chemoenzymatic procedures in the case of very small peptides, but, in many cases, production can be performed by biotechnological methods using genetically modified microorganisms (fermentation) or transgenic crops (plant biofactories).     

Microbial degradation of recalcitrant compounds and synthetic aromatic polymers

The evolution of microbial catabolic enzymes cannot keep pace with the rapid introduction of novel compounds into the environment. These new synthetic compounds that are slowly biodegradable or non-biodegradable are known as recalcitrant compounds, and range from simple halogenated hydrocarbons to complex polymers. Recalcitrant compounds can be made biodegradable by developing microorganisms capable of degrading the compound and by treating the compound to make it more conducive to mirobial attack. Many factors contribute to recalcitrance. The organism may lack the necessary genetic information. The organism can acquire this information by plasmid transfer or de novo enzyme synthesis. Plasmids have been characterized that degrade or transform antibiotics, pesticides, and hydrocarbons. By the use of chemostat techniques or chemical mutagens, organisms have been shown to synthesize de novo enzymes. The compound may be too large to enter the cell, or a transport system may not exist to transport it across the membrane. The compound may be insoluble, either as a solid or a liquid, and the microorganism may lack the proper nutrients. Recalcitrant compounds can be oxygenated prior to degradation, in the presence of a readily assimilable carbon source. In the absence of the assimilable carbon source, the recalcitrant compound is not degraded, or only very slowly. Examples of such co-oxidative metabolism are alkane and lignin degradation. Polymers, particularly synthetic ones, are prime examples of difficult-to-degrade compounds. The initial rate of polymer degradation follows a Freundlich or modified Langmuir isotherm rather than Michaelis-Menten kinetics. Microorganisms can irreversibly bind to solid surfaces by various methods. Soil microorganisms have been found to degrade styrene monomers and dimers. Polystyrene has been shown to be biodegradable by ¹⁴CO₂ evolution but at a very slow rate. In car tyres, styrene as a copolymer of butadiene is co-metabolized in the presence of other assimilable carbon sources.     

Design,functional evaluation and biomedical applications of carbohydrate dendrimers (glycodendrimers)

Receptors for carbohydrates of the lectin type are multisubunit and multivalent proteins with many important biological functions. In order to put their unique biological activities into use in biotechnology and biomedicine, efficient carbohydrate ligands of the glycodendrimer type have been constructed. Although these compounds may be branched into the multiple generations, structures bearing four to 16 terminal carbohydrate substituents have proved to be efficient ligands in most lectin systems. These compounds are rapidly finding important practical applications as antitumor and antiinfective compounds.     

Glycosidase inhibitors: inhibitors of N-linked oligosaccharide processing.

The biosynthesis of the various types of N-linked oligosaccharide structures involves two series of reactions: 1) the formation of the lipid-linked saccharide precursor, Glc3Man9(GlcNAc)2-pyrophosphoryl-dolichol, by the stepwise addition of GlcNAc, mannose and glucose to dolichyl-P, and 2) the removal of glucose and mannose by membrane-bound glycosidases and the addition of GlcNAc, galactose, sialic acid, and fucose by Golgi-localized glycosyltransferases to produce different complex oligosaccharide structures. For most glycoproteins, the precise role of the carbohydrate is still not known, but specific N-linked oligosaccharide structures are key players in targeting of lysosomal hydrolases to the lysosomes, in the clearance of asialoglycoproteins from the serum, and in some cases of cell:cell adhesion. Furthermore, many glycoproteins have more than one N-linked oligosaccharide, and these oligosaccharides on the same protein frequently have different structures. Thus, one oligosaccharide may be of the high-mannose type whereas another may be a complex chain. One approach to determining the role of specific structures in glycoprotein function is to use inhibitors that block the modification reactions at different steps, causing the cell to produce glycoproteins with altered carbohydrate structures. The function of these glycoproteins can then be assessed. A number of alkaloid-like compounds have been identified that are specific inhibitors of the glucosidases and mannosidases involved in glycoprotein processing. These compounds cause the formation of glycoproteins with glucose-containing high mannose structures, or various high-mannose or hybrid chains, depending on the site of inhibition. These inhibitors have also been useful for studying the processing pathway and for comparing processing enzymes from different organisms.     

Mini-review: Marine natural products and their synthetic analogs as antifouling compounds: 2009–2014

This review covers 214 marine natural compounds and 23 of their synthetic analogs, which were discovered and/or synthesized from mid-2009 to August 2014. The antifouling (AF) compounds reported have medium to high bioactivity (with a threshold of EC₅₀ < 15.0 mg ml^?1). Among these compounds, 82 natural compounds were identified as new structures. All the compounds are marine-derived, demonstrating that marine organisms are prolific and promising sources of natural products that may be developed as environmentally friendly antifoulants. However, this mini-review excludes more than 200 compounds that were also reported as AF compounds but with rather weak bioactivity during the same period. Also excluded are terrestrial-derived AF compounds reported during the last five years. A brief discussion on current challenges in AF compound research is also provided to reflect the authors’ own views in terms of future research directions.     

Synthesis and Characterization of Novel 1,3-Diaryltriazene-Substituted Sulfaguanidine Derivatives as Selective Carbonic Anhydrase Inhibitors: Biological Evaluation,in Silico ADME/T and Molecular Docking Study

Sulfonamide compounds known as human carbonic anhydrase (hCA) inhibitors are used in the treatment of many diseases such as epilepsy, antibacterial, glaucoma, various diseases. 1,3-diaryl-substituted triazenes and sulfaguanidine are used for therapeutic purposes in many drug structures. Based on these two groups, the synthesis of new compounds is important. In the present study, the novel 1,3-diaryltriazene-substituted sulfaguanidine derivatives ( SG1-13 ) were synthesized and fully characterized by spectroscopic and analytic methods. Inhibitory effect of these compounds on the hCA I and hCA II was screened as in vitro. All the series of synthesized compounds have been identified as potential hCA isoenzymes inhibitory with K_I values in the range of 6.44±0.74-86.85±7.01 nM for hCA I and with K_I values in the range of 8.16±0.40-77.29±9.56 nM for hCA II. Moreover, the new series of compounds showed a more effective inhibition effect than the acetazolamide used as a reference. The possible binding positions of the compounds with a binding affinity to the hCA I and hCA II was demonstrated by in silico studies. In conclusion, compounds with varying degrees of affinity for hCA isoenzymes have been designed and as selective hCA inhibitors. These compounds may be potential alternative agents that can be used to treat or prevent diseases associated with glaucoma and hCA inhibition.     

Identification of abelson tyrosine kinase inhibitors as potential therapeutics for Alzheimer’s disease using multiple e-pharmacophore modeling and molecular dynamics

Efforts to combat Alzheimer’s disease are focused predominantly on inhibiting the activity of the enzyme(s) that have been identified to be responsible for the production of the amyloid-forming peptide. However, the inherent complexity associated with the network of pathways leading to the disease may involve additional targets for designing effective therapies. Recent experimental findings have identified abelson tyrosine kinase, a non-receptor kinase as a new target for Alzheimer’s. In this work, we employed energy optimized multiple pharmacophore modeling strategy from multiple c-Abl structures bound with ligands in the inactive ATP binding conformation (DFG-out). Virtual screening followed by docking of molecules from ChemBridge resulted in the identification of 10 best scoring molecules. MD simulations of the top three complexes revealed that Compound A, C are the most stable complexes with the most persistent protein–ligand interactions consistent with the calculated binding affinities for the top three compounds. Given the implied role of c-Abl not only in AD but in Parkinson’s disease, the identified compounds may serve as leads for effective neurotherapeutics.     

Seven new bibenzyls and a dihydrochalcone from Radula variabilis

Six new bibenzyls have been isolated from the liverwort, Radula variabilis and their structures have been established by chemical and spectral evidence. In addition, a new dihydrochalcone and a new bibenzy] have been isolated as their methyl ethers. Except for two of the bibenzyls, the present compounds have a unique seven-membered heterocyclic ring and they are the first members of a new group of natural product.