Characterization and Metabolism of Drug Products Containing the Cocaine-Like New Psychoactive Substances Indatraline and Troparil.

With a rising demand of cocaine over the last years, it is likely that unregulated new psychoactive substances with similar effects such as indatraline ((1,3)-3-(3,4-dichlorophenyl)--methyl-2,3-dihydro-1-inden-1-amine) and troparil (Methyl (1,2,3,5)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate) become popular as well.

Discovery and overproduction of novel highly bioactive pamamycins through transcriptional engineering of the biosynthetic gene cluster.

Background: Pamamycins are a family of highly bioactive macrodiolide polyketides produced by Streptomyces alboniger as a complex mixture of derivatives with molecular weights ranging from 579 to 705 Daltons. The large derivatives are produced as a minor fraction, which has prevented their isolation and thus studies of chemical and biological properties.

Results: Herein, we describe the transcriptional engineering of the pamamycin biosynthetic gene cluster (pam BGC), which resulted in the shift in production profile toward high molecular weight derivatives.

Heterologous Production and Biosynthesis of Threonine-16:0dioic acids with a Hydroxamate Moiety.

Dereplication and genome mining in LU18118 combined with heterologous expression of selected biosynthetic gene clusters (BGCs) led to the discovery of various threonine-16:0dioic acids named lipothrenins. Lipothrenins consist of the core elements l-Thr, d--Thr, or Dhb, which are linked to hexadecanedioic acid by an amide bond. The main compound lipothrenin A () carries the -hydroxylated d- form of threonine and expresses a siderophore activity.

The calcium channel modulator 2-APB hydrolyzes in physiological buffers and acts as an effective radical scavenger and inhibitor of the NADPH oxidase 2.

2-aminoethoxydiphenyl borate (2-APB) is commonly used as a tool to modulate calcium signaling in physiological studies. 2-APB has a complex pharmacology and acts as activator or inhibitor of a variety of Ca channels and transporters. While unspecific, 2-APB is one of the most-used agents to modulate store-operated calcium entry (SOCE) mediated by the STIM-gated Orai channels.

Anion and ether group influence in protic guanidinium ionic liquids.

Ionic liquids are attractive liquid materials for many advanced applications. For targeted design, in-depth knowledge about their structure-property-relations is urgently needed. We prepared a set of novel protic ionic liquids (PILs) with a guanidinium cation with either an ether or alkyl side chain and different anions.

Furaquinocins K and L: Novel Naphthoquinone-Based Meroterpenoids from sp. Je 1-369.

Actinomycetes are the most prominent group of microorganisms that produce biologically active compounds. Among them, special attention is focused on bacteria in the genus . Streptomycetes are an important source of biologically active natural compounds that could be considered therapeutic agents.

Miramides A-D: Identification of Detoxin-like Depsipeptides after Heterologous Expression of a Hybrid NRPS-PKS Gene Cluster from Lu17588.

Natural products derived from plants, fungi or bacteria have been used for years in the medicine, agriculture and food industries as they exhibit a variety of beneficial properties, such as antibiotic, antifungal, anticancer, herbicidal and immunosuppressive activities. Compared to synthetic compounds, natural products possess a greater chemical diversity, which is a reason why they are profitable templates for developing pharmaceutical drug candidates and ongoing research on them is inevitable. Performing heterologous expression with unknown gene clusters is the preferred method to activate gene clusters that are not expressed in the wild-type strain under laboratory conditions; thus, this method offers a way to discover new interesting metabolites.

Formulation attributes, acid tunable degradability and cellular interaction of acetalated maltodextrin nanoparticles.

Exploiting materials for nanoparticle production has never halted to address the diversity in cargos and applications. Herein, maltodextrin (MD) was selected for being economic, nontoxic, biocompatible, and biodegradable. Different MDs were modified through acetal modification, turning the polymer hydrophobic and allowing pH-dependent tunable degradability.

New Scabimycins A-C Isolated from (Lu19992).

Peptide natural products displaying a wide range of biological activities have become important drug candidates over the years. Microorganisms have been a powerful source of such bioactive peptides, and have yielded many novel natural products thus far. In an effort to uncover such new, meaningful compounds, the metabolome of was analyzed thoroughly.

Bonsecamin: A New Cyclic Pentapeptide Discovered through Heterologous Expression of a Cryptic Gene Cluster.

The intriguing structural complexity of molecules produced by natural organisms is uncontested. Natural scaffolds serve as an important basis for the development of molecules with broad applications, e.g.

Cyclofaulknamycin with the Rare Amino Acid D-capreomycidine Isolated from a Well-Characterized Strain.

Targeted genome mining is an efficient method of biosynthetic gene cluster prioritization within constantly growing genome databases. Using two capreomycidine biosynthesis genes, alpha-ketoglutarate-dependent arginine beta-hydroxylase and pyridoxal-phosphate-dependent aminotransferase, we identified two types of clusters: one type containing both genes involved in the biosynthesis of the abovementioned moiety, and other clusters including only arginine hydroxylase. Detailed analysis of one of the clusters, the cluster from , led to the identification of a cyclic peptide that contains a rare D-capreomycidine moiety for the first time.

Discovery and Heterologous Production of New Cyclic Depsibosamycins.

are producers of valuable secondary metabolites with unique scaffolds that perform a plethora of biological functions. Nonribosomal peptides are of special interest due to their variety and complexity. They are synthesized by nonribosomal peptide synthetases, large biosynthetic machineries that are encoded in the genome of many species.

Metabolism of oral turinabol by the human brain cholesterol 24-hydroxylase CYP46A1.

The human microsomal cytochrome P450 enzyme CYP46A1 plays a crucial role in cholesterol elimination from the brain. It performs a 24-hydroxylation of cholesterol and is of outstanding significance for memory and cognition. This study demonstrates the catalytic activity of human CYP46A1 towards an anabolic androgenic steroid, oral turinabol (dehydrochloromethyltestosterone, 4-chloro-17β-dihydroxy,17α-methylandrosta-1,4-dien-3-one), which is a doping substance.

Targeted Genome Mining-From Compound Discovery to Biosynthetic Pathway Elucidation.

Natural products are an important source of novel investigational compounds in drug discovery. Especially in the field of antibiotics, Actinobacteria have been proven to be a reliable source for lead structures. The discovery of these natural products with activity- and structure-guided screenings has been impeded by the constant rediscovery of previously identified compounds.

Dudomycins: New Secondary Metabolites Produced After Heterologous Expression of an Nrps Cluster from ssp. Nrrl B-24108.

Since the 1950s, natural products of bacterial origin were systematically developed to be used as drugs with a wide range of medical applications. The available treatment options for many diseases are still not satisfying, wherefore, the discovery of new structures has not lost any of its importance. Beyond the great variety of already isolated and characterized metabolites, Streptomycetes still harbor uninvestigated gene clusters whose products can be accessed using heterologous expression in host organisms.

Loseolamycins: A Group of New Bioactive Alkylresorcinols Produced after Heterologous Expression of a Type III PKS from .

Natural products are a valuable source of biologically active compounds with potential applications in medicine and agriculture. Unprecedented scaffold diversity of natural products and biocatalysts from their biosynthetic pathways are of fundamental importance. Heterologous expression and refactoring of natural product biosynthetic pathways are generally regarded as a promising approach to discover new secondary metabolites of microbial origin.

Rapid Organocatalytic Formation of Carbon Monoxide: Application towards Carbonylative Cross Couplings.

Herein, the first organocatalytic method for the transformation of non-derivatized formic acid into carbon monoxide (CO) is introduced. Formylpyrrolidine (FPyr) and trichlorotriazine (TCT), which is a cost-efficient commodity chemical, enable this decarbonylation. Utilization of dimethylformamide (DMF) as solvent and catalyst even allows for a rapid CO generation at room temperature.

Studies on the In Vitro and In Vivo Metabolic Fate of the New Psychoactive Substance N-Ethyl-N-Propyltryptamine for Analytical Purposes.

Prerequisites for the reliable identification of substances in terms of forensic and clinical toxicology or doping control include knowledge about their metabolism and their excretion patterns in urine. N-Ethyl-N-propyltryptamine (N-ethyl-N-[2-(1H-indol-3-yl)ethyl]propan-1-amine, EPT) is an N,N-dialkylated tryptamine derivative, sold as new psychoactive substance, and supposed to act as a partial agonist at the 5-HT2A receptor. The aims of the presented study were to elucidate in vitro metabolites of EPT after incubations with pooled human liver S9 fraction (pS9) and in vivo metabolites excreted into rat urine.

Baikalomycins A-C, New Aquayamycin-Type Angucyclines Isolated from Lake Baikal Derived sp. IB201691-2A.

Natural products produced by bacteria found in unusual and poorly studied ecosystems, such as Lake Baikal, represent a promising source of new valuable drug leads. Here we report the isolation of a new sp. strain IB201691-2A from the Lake Baikal endemic mollusk .

Activity-guided isolation of cholinesterase inhibitors quercetin, rutin and kaempferol from fruit.

fruit is a source of anti-cholinesterase agents and led to an increase of acetylcholine levels in brain tissue as a usefull tool in the Alzheimer's disease therapy. This study aimed to propose a convenient method for the purification of cholinesterase inhibitors from water extract. Water extract from the fruit was ultrafiltered (0.

Benzanthric Acid, a Novel Metabolite From Del14 Expressing the Nybomycin Gene Cluster.

Streptomycetes constitute a diverse bacterial group able to produce a wide variety of secondary metabolites with potential applications in the pharmacy industry. However, the genes responsible for the biosynthesis of these compounds are very frequently inactive or expressed at very low levels under standard laboratory cultivation conditions. Therefore, the activation or upregulation of secondary metabolite biosynthesis genes is a crucial step for the discovery of new bioactive natural products.

Engineering of Streptomyces lividans for heterologous expression of secondary metabolite gene clusters.

Background: Heterologous expression of secondary metabolite gene clusters is used to achieve increased production of desired compounds, activate cryptic gene clusters, manipulate clusters from genetically unamenable strains, obtain natural products from uncultivable species, create new unnatural pathways, etc. Several Streptomyces species are genetically engineered for use as hosts for heterologous expression of gene clusters. S.

Transport properties of protic and aprotic guanidinium ionic liquids.

Ionic liquids (ILs) are a promising class of solvents, functional fluids and electrolytes that are of high interest for both basic as well as applied research. For further fundamental understanding of ILs and a successful implementation in technical processes, a deeper insight into transport properties and their interrelations is of particular importance. In this contribution we synthesised a series of mostly novel protic and aprotic ILs based on the tetramethylguanidinium (TMG) cation that is a derivative of the superbase guanidine.

Multiple Ether-Functionalized Phosphonium Ionic Liquids as Highly Fluid Electrolytes.

Ionic liquids (ILs) are promising electrolytes, although their often high viscosity remains a serious drawback. The latter can be addressed by the introduction of multiple ether functionalization. Based on the highly atom efficient synthesis of tris(2-ethoxyethyl) phosphine, several new phosphonium ionic liquids were prepared, which allows studying the influence of the ether side chains.

New Alpiniamides From sp. IB2014/011-12 Assembled by an Unusual Hybrid Non-ribosomal Peptide Synthetase -AT Polyketide Synthase Enzyme.

The environment of Lake Baikal is a well-known source of microbial diversity. The strain sp. IB2014/011-12, isolated from samples collected at Lake Baikal, was found to exhibit potent activity against Gram-positive bacteria.