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Seven new alkaloids [1, (±)-2, (±)-3, 4, and 5] and one new natural product (6), along with eight known analogues, were isolated from the tubers of Pinellia pedatisecta Schott. Their structures were determined by a comprehensive analysis of spectroscopic data, including HRESIMS, and electronic circular dichroism (ECD). In addition, the results of the bioactivity evaluation showed that compounds (±)-3, 6, and 9 exhibited significantly protective effects against Aβ [sub.25-35]-induced PC-12 cell injury and ameliorated cell viabilities by decreasing the levels of the reactive oxidative species (ROS) and mitochondrial membrane potential (MMP).

Lupinus mutabilis, also known as tarwi or chocho, is an important agricultural species that has been cultivated in South America since ancient times. Tarwi is native to the Andean regions of Peru, Bolivia, and Ecuador and has very high protein content. Despite its high nutritional value and promotion efforts by regional researchers and breeders, tarwi is not a widely cultivated crop in its center of origin. In this review, we present the work carried out by public breeding programs of L. mutabilis at national agricultural research institutes, universities, and other institutions in Ecuador, Peru, and Bolivia. The main breeding method used in the Andes to improve local landraces has been mass selection to adapt lines to specific environments. At least 25 cultivars or ecotypes have been selected and released over the last 40 years using this breeding system. Nevertheless, breeders are currently struggling to develop new varieties that are high yielding, suitable for mechanized harvesting, have a low content of alkaloids or other anti-nutritional properties, and resistant to anthracnose (Colletotrichum acutatum). Therefore, it is necessary to reassess the potential of this crop and invest in its research to incorporate new techniques and breeding strategies to optimize the development of new varieties in the Andes which address the current cultivation challenges of the species.

The present paper describes a novel two-dimensional liquid chromatography (2D-LC) system, which is comprised of a first-dimensional ion exchange chromatography (IEX1) column, trap column, and second-dimensional reversed-phase chromatography (RP2) column system. The biological sample is separated by the first-dimensional LC using an IEX column to remove interferences. The analytes are transferred to the trap column after heart-cutting. Then, the analytes are transferred to the second-dimensional LC using an RP2 column for further separation and ultraviolet detection. This 2D-LC system can offer a large injection volume to provide sufficient sensitivity and exhibits a strong capacity for removing interferences. Here, the determination of three monoterpene indole alkaloids (MIAs; gelsemine, koumine, and humantenmine) from Gelsemium in biological matrices (plasma, tissue, and urine) was used this 2D-LC system. After a rapid and easy sample preparation method based on protein precipitation, the sample was injected into the 2D-LC. The method was developed and validated in terms of the selectivity, LOD, LOQ, linearity, precision, accuracy, and stability. The sample preparation time for the three MIAs was 15 min. The LOD for these compounds was 10 ng/mL, which was lower than the developed HPLC methods. The results showed that this method had good quantitation performance and allowed the determination of gelsemine, koumine, and humantenmine in biological matrices. The method is rapid, exhibits high selectivity, has good sensitivity, and is low-cost, thus making it well-suited for application in the pharmaceutical and toxicological analysis of Gelsemium.

Many natural products that contain basic nitrogen atoms—for example alkaloids like morphine and quinine—have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously. Natural products citrinalin B and cyclopiamine B, which contain basic nitrogen atoms that are susceptible to oxidation during synthesis, can be synthesized by the selective introduction and removal of functional groups. Novel nitrogen-containing natural products synthesized This paper reports the first syntheses of the natural products citrinalin B and cyclopiamine B. And as a by-product of this work, the authors propose a revision of the structure initially assigned to citrinalin B. The presence of nitrogen atoms in a target molecule can complicate its synthesis because of nitrogen's basicity and susceptibility to oxidation. This can be circumvented by the selective introduction and removal of functional groups that mitigate basicity. The prenylated indole alkaloids citrinalin B and cyclopiamine B were produced using a refinement of the technique, opening up a class of compounds that includes therapeutics such as quinine and morphine to synthetic chemistry.

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some-including the infamous ergot alkaloids-have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses.

Mitragynine is an “atypic opioid” analgesic with an alternative mechanism of action and a favorable side-effect profile. Our aim was to optimize the alkaloid extraction procedure from kratom leaves and to determine and isolate the most relevant compounds capable of penetrating the central nervous system. The PAMPA-BBB study revealed that mitragynine and its coalkaloids, speciociliatine, speciogynine, and paynantheine, possess excellent in vitro BBB permeability. An optimized sequence of CPC, flash chromatography, and preparative HPLC methods was used to isolate the four identified BBB+ alkaloids. To improve the bioavailability of the isolated alkaloids, their cyclodextrin (CD) complexation behavior was investigated via affinity capillary electrophoresis using almost 40 CD derivatives. The apparent alkaloid–CD complex stability constants were determined and compared, and the most relevant CDs phase-solubility studies were also performed. Both the neutral and negatively charged derivatives were able to form complexes with all four kratom alkaloids. It was found that cavity size, substituent type, and degree of substitution also influenced complex formation. The negatively charged Sugammadex, Subetadex, and the sufoalkylated-beta-CD analogs were able to form the most stable complexes, exceeding 1000 M−1. These results serve as a good basis for further solubility and stability enhancement studies of kratom alkaloids.

Vinblastine and vincristine are important, expensive anticancer agents that are produced by dimerization of the plant-derived alkaloids catharanthine and vindoline. The enzymes that transform tabersonine into vindoline are known; however, the mechanism by which the scaffolds of catharanthine and tabersonine are generated has been a mystery. Caputi et al. now describe the biosynthetic genes and corresponding enzymes responsible. This resolves a long-standing question of how plant alkaloid scaffolds are synthesized, which is important not only for vinblastine and vincristine biosynthesis, but also for understanding the many other biologically active alkaloids found throughout nature. Science , this issue p. 1235 Identification of enzymes reveals pathway complexity in synthesis of bioactive alkaloids from plants. Vinblastine, a potent anticancer drug, is produced by Catharanthus roseus (Madagascar periwinkle) in small quantities, and heterologous reconstitution of vinblastine biosynthesis could provide an additional source of this drug. However, the chemistry underlying vinblastine synthesis makes identification of the biosynthetic genes challenging. Here we identify the two missing enzymes necessary for vinblastine biosynthesis in this plant: an oxidase and a reductase that isomerize stemmadenine acetate into dihydroprecondylocarpine acetate, which is then deacetoxylated and cyclized to either catharanthine or tabersonine via two hydrolases characterized herein. The pathways show how plants create chemical diversity and also enable development of heterologous platforms for generation of stemmadenine-derived bioactive compounds.

Pyrrolizidine alkaloids (PAs) are among the most potent phytotoxins widely distributed in plant species around the world. PA is one of the major causes responsible for the development of hepatic sinusoidal obstruction syndrome (HSOS) and exerts hepatotoxicity via metabolic activation to form the reactive metabolites, which bind with cellular proteins to generate pyrrole-protein adducts, leading to hepatotoxicity. PA N -oxides coexist with their corresponding PAs in plants with varied quantities, sometimes even higher than that of PAs, but the toxicity of PA N -oxides remains unclear. The current study unequivocally identified PA N -oxides as the sole or predominant form of PAs in 18 Gynura segetum herbal samples ingested by patients with liver damage. For the first time, PA N -oxides were recorded to induce HSOS in human. PA N -oxide-induced hepatotoxicity was further confirmed on mice orally dosed of herbal extract containing 170 μmol PA N -oxides/kg/day, with its hepatotoxicity similar to but potency much lower than the corresponding PAs. Furthermore, toxicokinetic study after a single oral dose of senecionine N -oxide (55 μmol/kg) on rats revealed the toxic mechanism that PA N -oxides induced hepatotoxicity via their biotransformation to the corresponding PAs followed by the metabolic activation to form pyrrole-protein adducts. The remarkable differences in toxicokinetic profiles of PAs and PA N -oxides were found and attributed to their significantly different hepatotoxic potency. The findings of PA N -oxide-induced hepatotoxicity in humans and rodents suggested that the contents of both PAs and PA N -oxides present in herbs and foods should be regulated and controlled in use.

The effects of sympathetic cotransmitter [NAD.sup.+] (10 [micro]M) on bioelectric activity of the heart under conditions of adrenergic stimulation were studied on isolated spontaneously contracting preparations (without stimulation) of the right atrium from 2-7-day-old rats. Action potentials were recorded in the working myocardium using standard microelectrode technique. Perfusion of the right atrium with norepinephrine solution (1 [micro]M) altered the configuration and significantly lengthened the action potentials. [NAD.sup.+] against the background of norepinephrine stimulation significantly decreased the duration of action potentials, in particular, at 25% repolarization. The effect of purine compounds [NAD.sup.+], ATP, and adenosine on bioelectrical activity of the heart of newborn rats was studied under basal conditions (without norepinephrine stimulation). The effect of [NAD.sup.+] against the background of adrenergic stimulation was more pronounced than under basal conditions and was probably determined by suppression of [I.sub.CaL], which can be the main mechanism of [NAD.sup.+] action on rat heart. Key Words: action potentials; rat atrium myocardium; adrenergic stimulation; [NAD.sup.+]; ontogeny

Tropane alkaloids from nightshade plants are neurotransmitter inhibitors that are used for treating neuromuscular disorders and are classified as essential medicines by the World Health Organization 1 , 2 . Challenges in global supplies have resulted in frequent shortages of these drugs 3 , 4 . Further vulnerabilities in supply chains have been revealed by events such as the Australian wildfires 5 and the COVID-19 pandemic 6 . Rapidly deployable production strategies that are robust to environmental and socioeconomic upheaval 7 , 8 are needed. Here we engineered baker’s yeast to produce the medicinal alkaloids hyoscyamine and scopolamine, starting from simple sugars and amino acids. We combined functional genomics to identify a missing pathway enzyme, protein engineering to enable the functional expression of an acyltransferase via trafficking to the vacuole, heterologous transporters to facilitate intracellular routing, and strain optimization to improve titres. Our integrated system positions more than twenty proteins adapted from yeast, bacteria, plants and animals across six sub-cellular locations to recapitulate the spatial organization of tropane alkaloid biosynthesis in plants. Microbial biosynthesis platforms can facilitate the discovery of tropane alkaloid derivatives as new therapeutic agents for neurological disease and, once scaled, enable robust and agile supply of these essential medicines. The alkaloid drugs hyoscyamine and scopolamine are synthesized from sugars and amino acids in yeast, using 26 genes from yeast, plants, bacteria and animals, protein engineering and a vacuole transporter to enable functional expression of a key acyltransferase.