Variety Of Alkaloids Research Articles

Intraspecific Variation in the Alkaloids of Adalia decempunctata (Coleoptera, Coccinellidae): Sex, Reproduction and Colour Pattern Polymorphism

In this paper, we examine intraspecific variation in the quantity of alkaloid chemical defence in field collected individuals of the polymorphic ladybird beetle Adalia decempunctata (10-spot ladybird). Like its more widely studied relative Adalia bipunctata (2-spot ladybird), A. decempunctata possesses the alkaloids adaline and adalinine, which are, respectively, the major and minor alkaloids of A. bipunctata. We focused especially on alkaloid concentration in relation to colour pattern morph, sex, and the relationship between female and egg parameters. There was a marked sexual dimorphism in the balance of the two alkaloids, with adaline predominating in females and adalinine predominating in males: in males, on average, over 70% of total alkaloid was adalinine. Females had a lower proportion of adalinine (< 10%) than their eggs (> 15%) and relationships between egg alkaloid and female alkaloid or fecundity were weak or non-existent. Colour pattern morph had a borderline (although not) significant relationship with adaline concentration and total alkaloid concentration, which could be further explored with laboratory reared individuals. The sexual dimorphism in alkaloid content, which seems likely due to differences in synthesis, might be related to their relative costs to the two sexes and might provide insight into the evolution of alkaloid diversity in ladybirds.

A developmental gradient reveals biosynthetic pathways to eukaryotic toxins in monocot geophytes

Numerous eukaryotic toxins that accumulate in geophytic plants are valuable in the clinic, yet their biosynthetic pathways have remained elusive. A notable example is the >150 Amaryllidaceae alkaloids (AmAs), including galantamine, an FDA-approved treatment for Alzheimer's disease. We show that while AmAs accumulate to high levels in many daffodil tissues, biosynthesis is localized to nascent, growing tissue at the leaf base. A similar trend is found in the production of steroidal alkaloids (e.g., cyclopamine) in corn lily. This model of active biosynthesis enabled the elucidation of a complete set of biosynthetic genes that can be used to produce AmAs. Taken together, our work sheds light on the developmental and enzymatic logic of diverse alkaloid biosynthesis in daffodils. More broadly, it suggests a paradigm for biosynthesis regulation in monocot geophytes, where plants are protected from herbivory through active charging of newly formed cells with eukaryotic toxins that persist as above-ground tissue develops.

The Clausena lansium genome provides new insights into alkaloid diversity and the evolution of the methyltransferase family

Wampee (Clausena lansium) is an important evergreen fruit tree native to southern China that has a long history of use for medicinal purposes. Here, a chromosome-level genome of C. lansium was constructed with a genome size of 282.9 Mb and scaffold N50 of 30.75 Mb. The assembled genome contains 48.70% repetitive elements and 24,381 protein-coding genes. Comparative genomic analysis showed that C. lansium diverged from Aurantioideae 15.91–24.95 million years ago. Additionally, some expansive and specific gene families related to methyltransferase activity and S-adenosylmethionine-dependent methyltransferase activity were also identified. Further analysis indicated that N-methyltransferase (NMT) is mainly involved in alkaloid biosynthesis and O-methyltransferase (OMT) participates in the regulation of coumarin accumulation in wampee. This suggested that wampee's richness in alkaloids and coumarins might be due to the gene expansions of NMT and OMT. The tandem repeat event was one of the major reasons for the NMT expansion. Hence, the reference genome of C. lansium will facilitate the identification of some useful medicinal compounds from wampee resources and reveal their biosynthetic pathways.

Discovery and Characterization of Epichloë Fungal Endophytes from Elymus spp. in Northwest China.

Epichloë fungal endophytes hold promise in sustainable agriculture by fortifying cool-season grasses such as Elymus spp. against various stresses. Elymus spp. are widely distributed in Northwest China with a high incidence of endophyte infections. In this study, we identified 20 Epichloë endophytic fungal strains carried by five Elymus spp. from five areas of Northwest China and systematically characterized their morphology, molecular phylogeny, mating type, and alkaloid diversity for the first time. The morphological characterization underscores strain diversity, with variable colony textures and growth rates. A phylogenetic analysis confirms all strains are E. bromicola, emphasizing their taxonomic status. Alkaloid-encoding gene profiling delineates distinct alkaloid synthesis capabilities among the strains, which are crucial for host adaptability and resistance. A mating-type analysis reveals uniformity (mtAC) across the Epichloë strains, simplifying breeding strategies. Notably, the Epichloë strains exhibit diverse alkaloid synthesis gene profiles, impacting host interactions. This research emphasizes the ecological significance of Epichloë endophytes in Elymus spp. ecosystems, offering insights into their genetic diversity and potential applications in sustainable agriculture.

Glycoalkaloids: Structural diversity and pharmacological activities

Glycoalkaloids (GAs) are a class of special secondary metabolites found in plants. Studies have found that they have a wide range of pharmacological activities, such as antiviral, antifungal, and anticancer properties, with significant potential for development and utilization value. At present, alkaloid glucosides mainly fall into 2 categories: indole alkaloid glucosides and steroid alkaloid glucosides. In addition, there are small amounts of quinolines, isoquinolines, isoguanines, and other alkaloids. At present, only a few of the GAs have been found, which is inconsistent with the diversity of alkaloids. In addition, only a few GAs have been isolated and identified. This paper reviews the natural alkaloid glycosides from the perspectives of structural classification and pharmacological activity. It analyzes the reasons for the limited number of isolated components and proposes a rational separation method based on the literature. To provide references for the separation, identification, and bioactivity of glycoalkaloids.

Discovery and identification of natural alkaloids with potential to impact insulin resistance syndrome in Cyclocarya paliurus. (Batal) leaves by UPLC-QTOF-MS combined with HepG2 cells

Cyclocarya paliurus (Batal.) leaves, which contain a range of bioactive compounds, have been used as a traditional Chinese medicine homologous food since ancient times. However, there is a paucity of literature on comprehensive studies of alkaloids in the leaves of Cyclocarya paliurus (Batal.). For the first time, this study aimed to discover and identify alkaloids extracted from Cyclocarya paliurus (Batal.) leaves by ultra-high performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UPLC-QTOF-MS). A total of ten alkaloids have been identified from Cyclocarya paliurus (Batal.) leaves based on accurate mass spectra (mass accuracy, isotopic spacing and distribution) and comparison to fragmentation spectra reported in the literature. In vitro, alkaloids alleviated insulin resistance by increasing glucose consumption and glycogen content in insulin resistance HepG2 cells. The RNA-seq and western blotting results showed that alkaloids could upregulate the expression of phosphatidylinositol 3-kinase (PI3K), and increase the phosphorylation of insulin receptor protein kinase B (AKT). This study not only clarified the chemical constituents and revealed that diverse alkaloids also presented from Cyclocarya paliurus (Batal.) leaves, also, it will provide chemical information on potential compounds for developing new drugs.

Chemical Diversity of Indole Alkaloids from Malaysian Kopsia Species (Apocynaceae) and Their Biological Activities

The genus Kopsia, which belongs to the family Apocynaceae, has been used extensively in traditional treatment. This mini-review provides a comprehensive analysis of the chemical diversity of indole alkaloids from Malaysian Kopsia species and their biological activities. Fifteen species with 164 indole alkaloids have already been studied and successfully isolated and characterised. Most of them are categorised as aspidofractinine, aspidospermane and eburnane types. The literature and references for this manuscript were obtained from various sources including SciFinder®, Reaxys®, ScienceDirect®, PubMed Central®, NIH National Library of Medicine, Google Scholar and The Plant List®.

Lineage-Specific CYP80 Expansion and Benzylisoquinoline Alkaloid Diversity in Early-Diverging Eudicots.

Menispermaceae species, as early-diverging eudicots, can synthesize valuable benzylisoquinoline alkaloids (BIAs) like bisbenzylisoquinoline alkaloids (bisBIAs) and sinomenines with a wide range of structural diversity. However, the evolutionary mechanisms responsible for their chemo-diversity are not well understood. Here, a chromosome-level genome assembly of Menispermum dauricum is presented and demonstrated the occurrence of two whole genome duplication (WGD) events that are shared by Ranunculales and specific to Menispermum, providing a model for understanding chromosomal evolution in early-diverging eudicots. The biosynthetic pathway for diverse BIAs in M. dauricum is reconstructed by analyzing the transcriptome and metabolome. Additionally, five catalytic enzymes - one norcoclaurine synthase (NCS) and four cytochrome P450 monooxygenases (CYP450s) - from M. dauricum are responsible for the formation of the skeleton, hydroxylated modification, and C-O/C-C phenol coupling of BIAs. Notably, a novel leaf-specific MdCYP80G10 enzyme that catalyzes C2'-C4a phenol coupling of (S)-reticuline into sinoacutine, the enantiomer of morphinan compounds, with predictable stereospecificity is discovered. Moreover, it is found that Menispermum-specific CYP80 gene expansion, as well as tissue-specific expression, has driven BIA diversity in Menispermaceae as compared to other Ranunculales species. This study sheds light on WGD occurrences in early-diverging eudicots and the evolution of diverse BIA biosynthesis.

A nitrogenous heterocyclic ring-bonded stationary phase for separating alkaloids in supercritical fluid chromatography

A novel silica stationary phase was designed and prepared through thiol-epoxy click chemistry for supercritical fluid chromatography (SFC). The developed stationary phase was characterized by elemental analysis, Fourier transform infrared spectrometry and solid-state 13C/CP MAS NMR spectroscopy. In order to evaluate the chromatographic performance and retention mechanisms of the prepared column, a variety of alkaloids were used, including indoles, isoquinolines, pyrrolidines, piperidines, quinolizidines and organic amines. The stationary phase showed more symmetrical peak shapes and better performance for these compounds compared to the conventional SFC stationary phases. The investigations on the effects of pressure and temperature on retention provided information that the selectivity of the compounds can be improved by changing the density of the supercritical fluids. Moreover, it shows improved separation efficiency of three natural products with alkaloids as the main components at high sample loading. In conclusion, the developed stationary phase could offer flexible selectivity toward alkaloids and complex samples.

Transcriptome and metabolome analysis reveal the dynamic changes and biosynthesis pathways of alkaloids in Sophora alopecuroides L. under drought stress

Sophora lopecuroides L. is a medicinal plant containing a variety of biologically active substances, in which alkaloids are the main active substances, and a variety of alkaloids have been identified in S. alopecuroides. Drought stress can stimulate the accumulation of biologically active substances in medicinal plants. In this respect, the imposition of appropriate degree of drought stress may be an effective way to increase the alkaloid content in S. alopecuroides. However, the changes in the types and abundance of alkaloids in S. alopecuroides under drought stress and the molecular mechanism of regulating alkaloid biosynthesis are still unclear. In this study, the metabolome and transcriptome analysis were conducted to explore the influence of mild (D1), moderate (D2), and severe (D3) drought stress on the types and abundance of alkaloids in S. alopecuroides, and to identify the key regulatory genes in the alkaloid synthesis pathways. The results showed that the total alkaloid content in S. alopecuroides in the D1 and D2 group significantly decreased by 13.49% and 10.40%, respectively compared with that in the control group, but the total alkaloid content in S. alopecuroides in the D3 group significantly increased by 8.16% compared with that in the control group. Sixty-eight alkaloids were identified in S. alopecuroides, with quinolizidine alkaloids being the main type of alkaloids. Of the 25 differentially accumulated metabolites (DAMs), the number of DAMs with increased relative abundance in the D1, D2, and D3 group were 0, 7, and 20, respectively. The relative abundance of 6 DAMs increased in both D2 and D3 group, and 14 DAMs only increased in the D3 group such as methoxyindoleacetic acid, indole, and piperidine. Besides, the biosynthetic pathways of three major types of alkaloids (quinolizidine-, piperidine-, and plumerane-type alkaloids) were illustrated, and key genes (i.e., asd, DapL, PrAOs, DDC, and ALDH) associated with the alkaloid biosynthesis were identified. This study also found that 22 TFs (SaERF1∼SaERF5, SaWRKY1∼SaWRKY3, SabHLH1∼SabHLH3, SaMYB1∼SaMYB6, SabZIP1∼SabZIP5) were positively correlated with the alkaloid biosynthesis. This study deepens our understanding of the molecular mechanism of S. alopecuroides in response to drought stress, and helps to develop biotechnology strategies to manipulate the level of alkaloids in S. alopecuroides.

Monoterpenoid indole alkaloids from Alstonia scholaris and their Toxoplasma gondii inhibitory activity

Nine previously unreported various types of monoterpenoid indole alkaloids, together with seven known analogues were isolated from the stem barks of Alstonia scholaris through a silica gel free methodology. The structures of 1–9 were elucidated by spectroscopic data analysis, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Compound 1 is a modified echitamine-type alkaloid with a novel 6/5/5/7/6/6 hetero hexacyclic bridged ring system, and 8 and 9 exist as a zwitterion and trifluoroacetate salt, respectively. The anti-Toxoplasma activity of all isolates on infected Vero cells were evaluated, which revealed that compound 14 at 0.24 μM displayed potent activity. This study expanded the structural diversity of alkaloids of A. scholaris, and presented their potential application in anti-Toxoplasma drug development.

Modular assembly of an artificially concise biocatalytic cascade for the manufacture of phenethylisoquinoline alkaloids

Plant-derived alkaloids are an important class of pharmaceuticals. However, they still rely on phytoextraction to meet their diverse market demands. Since multistep biocatalytic cascades have begun to revolutionize the manufacture of natural or unnatural products, to address the synthetic challenges of alkaloids, herein we establish an artificially concise four-enzyme biocatalytic cascade with avoiding plant-derived P450 modification for synthesizing phenethylisoquinoline alkaloids (PEIAs) after enzyme discovery and enzyme engineering. Efficient biosynthesis of diverse natural and unnatural PEIAs is realized from readily available substrates. Most importantly, the scale-up preparation of the colchicine precursor (S)-autumnaline with a high titer is achieved after replacing the rate-limiting O-methylation by the plug-and-play strategy. This study not only streamlines future engineering endeavors for colchicine biosynthesis, but also provides a paradigm for constructing more artificial biocatalytic cascades for the manufacture of diverse alkaloids through synthetic biology.

Liriogerphines E–U, further unique sesquiterpene-alkaloid hybrids from the rare Chinese tulip tree

Seventeen undescribed sesquiterpene-alkaloid hybrids (liriogerphines E–U, 1–17) were isolated and identified during a further phytochemical investigation on the branches and leaves of Chinese tulip tree (Liriodendron chinense), a rare medicinal and ornamental plant endemic to China. These unique heterodimers are conjugates of germacranolide-type sesquiterpenoids with structurally diverse alkaloids [i.e., aporphine- (1–15), proaporphine- (16), and benzyltetrahydroisoquinoline-type (17)] via the formation of a C–N bond. The previously undescribed structures were elucidated by comprehensive spectroscopic data analyses and electronic circular dichroism calculations. Such a class of sesquiterpene-alkaloid hybrids presumably biosynthesized via an aza-Michael addition is quite rare from terrestrial plants. In particular, the sesquiterpene-benzyltetrahydroisoquinoline hybrid skeleton has never been reported until the present study. All the isolates were evaluated for their cytotoxic effects against a small panel of leukemia cell lines (Raji, Jeko-1, Daudi, Jurkat, MV-4-11 and HL-60), and some of them exhibited considerable activities.

Phytochemical Screening, Antioxidant Capacity Measurement, and Mineral Content Determination of Thymus vulgaris L. Extracts

The aim of this study was to evaluate the chemical composition and antioxidant activity of Thymus vulgaris L. extracts. T. vulgaris L. is a medicinal plant that has various bioactive compounds. Four different solvents (ethanol, water, ethyl acetate, and chloroform) were used to extract these compounds from the plant. The phytochemical screening of the extracts showed that the ethanolic extract had the highest diversity of compounds, including coumarins, flavonoids, alkaloids, tannins, phenols, carbohydrates, and proteins. The total phenolic and total antioxidant contents of the ethanolic extract were measured by the Folin–Ciocalteu and phosphomolybdenum methods, respectively. The ethanolic extract had a high phenolic content of 77.7 mg gallic acid equivalent/g dry weight, which indicates its potential antioxidant capacity. The mineral content of T. vulgaris L. was also assessed by flame photometry and atomic absorption spectrophotometry after dry digestion. The plant contained five macroelements (K, Na, Ca, Mg, P) and three microelements (Fe, Cu, Zn) in different concentrations. The highest concentration was found for potassium (15259 mg/kg), followed by calcium (5118 mg/kg) and sodium (4793 mg/kg). The lowest concentration was found for phosphorus (1400 mg/kg), which was still higher than the microelements. Among the microelements, zinc had the highest concentration (24.82 mg/kg), followed by iron (17.44 mg/kg) and copper (14.98 mg/kg). The results of this study provide useful information for the users, collectors and practitioners of medicinal plants from polluted areas, as they can evaluate the quality and safety of T. vulgaris L. for human consumption.

A biosynthetic network for protoberberine production in Coptis chinensis.

Protoberberine alkaloids are a group of tetracyclic isoquinoline compounds known for their well-established antimicrobial and anti-inflammatory properties. The richness and diversity of protoberberine alkaloids accumulated in the Coptis genus necessitate a comprehensive examination of the biosynthetic machinery to understand their ecological significance. Here, from Coptis chinensis we identified CcCYP719A1, which could install a methylenedioxy bridge on either ring A or ring D of the protoberberine backbone, thus diverging metabolite flux towards the biosynthesis of various protoberberine components. We also obtained CcCYP719A2 and CcCYP719A3, which underwent positive selection after diverging from CcCYP719A1 and maintained specific catalytic activity on ring D. Further, we resolved the biosynthetic pathway of jatrorrhizine by identifying two demethylases, which could also modulate protoberberine composition by removing the C-3 methyl group and methylenedioxy bridge of ring D, allowing demethylated metabolites to be redirected into different routes. Moreover, we characterized 2-O-methyltransferase CcOMT1 and flavin-dependent oxidase CcTHBO, respectively responsible for the commonly observed 2-O-methylation and aromatic ring-C assembly in protoberberine alkaloids. Overall, this study reveals an interconnected metabolite network from which diverse protoberberine alkaloids originate. It provides valuable insights into the existence of undiscovered protoberberine components, and paves the way for the targeted production of desired protoberberine components for potential therapeutic development.

Alkaloid diversity expansion of a talent fungus Penicillium raistrichii through OSMAC-based cultivation.

Alkaloidal natural products are attractive for their broad spectrum of pharmaceutical bioactivities. In the present work, the highly productive saline soil derived fungus, Penicillium raistrichii, was subjected to the strategy of OSMAC (one strain many compounds) with changes of cultivation status. Then, the work-flow led to the expansion of the alkaloid chemical diversity and subsequently induced the accumulation of four undescribed alkaloids, named raistrimides A-D (1-4), including three β-carbolines (1-3), one 2-quinolinone (4), and one new natural product, 2-quinolinone (5), along with five known alkaloid chemicals (6-10). A set of NMR techniques including 1H, 13C, HSQC and HMBC, along with other spectroscopic data of UV-Vis, IR and HRESIMS, were introduced to assign the plain structures of compounds 1-10. The absolute configuration of 1-3 were elucidated by means of X-ray crystallography or spectroscopic analyses on optical rotation values and experimental electronic circular dichroism (ECD) data. In addition, it was the first report on the confirmation of structures of 6, 7 and 9 by X-ray crystallography data. The micro-broth dilution method was applied to evaluate antimicrobial effect of all compounds towards Staphylococcus aureus, Escherichia coli, and Candida albicans. The results indicated compounds 1, 3 and 4 to be bioactive, which may be potential for further development of anti-antimicrobial agents. The finding in this work implied that OSMAC strategy was a powerful and effective tool for promotion of new chemical entities from P. raistrichii.

Auxin and light-mediated regulation of growth, morphogenesis, and alkaloid biosynthesis in Crinum x powellii ‘Album’ callus

Crinum x powellii ‘Album’ belongs to the Amaryllidaceae medicinal plant family that produces a range of structurally diverse alkaloids with potential therapeutic properties. The optimal conditions for in vitro tissue growth, morphogenesis, and alkaloid biosynthesis remain unclear. Auxin and light play critical roles in regulating plant growth, development, and alkaloid biosynthesis in several Amaryllidaceae plants. Here, we have succeeded in showing, for the first time, that the combination of auxin and light significantly influence C. x powellii “Album” in vitro tissue growth, survival, and morphogenesis compared to individual treatments. Furthermore, this combination also upregulates the expression of alkaloid biosynthetic genes and led to an increase in the content of certain alkaloids, suggesting a positive impact on the defense and therapeutic potential of the calli. Our findings provide insights into the regulation of genes involved in alkaloid biosynthesis in C. x powellii “Album” callus and underline the potential of auxin and light as tools for enhancing their production in plants. This study provides a foundation for further exploration of C. x powellii “Album” calli as a sustainable source of bioactive alkaloids for pharmaceutical and agricultural applications. Furthermore, this study paves the way to the discovery of the biosynthetic pathway of specialized metabolites from C. x powellii “Album”, such as cherylline and lycorine.

Comparative Transcriptome Analysis Reveals Genes Associated with Alkaloid Diversity in Javanese Long Pepper (Piper retrofractum) Fruits

Alkaloids are a class of secondary metabolites that play multifaceted roles in plant physiology, including defense mechanisms and interactions with other organisms. The alkaloids from Piper retrofractum (Javanese long pepper) fruits offer potential alternatives to synthetic pesticides due to their natural origin and insecticide properties. However, information on particular alkaloid biosynthesis pathways is required to enhance individual alkaloid production via metabolic engineering. Here, we perform HPLC profiling to demonstrate that fruit ripening influences the alkaloid diversity in P. retrofractum. De novo transcriptomic profiling of young, green mature, and red ripened fruits revealed that the piperine biosynthesis pathway genes were highly upregulated in the mature fruits. However, an enhanced accumulation of methyl piperate and guineensine in the ripened fruit was observed, entailing ripening-related differential gene expression to synchronize the alkaloid biosyntheses. Gene expression clustering and functional enrichment analysis identified a large group of genes involved in diverse biosynthetic processes explicitly enriched in the ripened fruits. A cohort of genes encoding for “Alkaloid Biosynthesis”, remarkably upregulated in the ripening fruits, indicates they may function directly in alkaloid diversity during a later stage of fruit development. This study provides the basis for metabolic engineering to enhance alkaloid diversity and production.

Antioxidant and anti-Alzheimer activities of Clivia miniata (Lindl) roots, bulbs, and aerial parts: In-vitro and in-silico studies

Clivia miniata (Lindl) is a member of the family Amaryllidaceae known for its chemically diverse alkaloids with a wide range of biological activities. Many reports revealed a direct role of oxidative stress in the early stage of Alzheimer’s disease (AD). Meanwhile, β-site amyloid precursor protein cleavage enzyme 1 (BACE-1) is a molecular target for the treatment of AD. We aimed to investigate C. miniata root, bulb, and aerial part chemical profiling, antioxidant, BACE-1, and AChE enzyme inhibitory activities. Results showed that the total root had the most potent radical scavenging activity as compared to the total bulb and aerial part, respectively. Ethanol root extract had the most potent BACE-1 inhibitory activity (IC50 = 0.02 ± 0.001 µg/mL) as compared to the bulb and aerial part (IC50 = 0.93 ± 0.13, 1.80 ± 0.24 µg/mL), respectively. Moreover, the total root extract mitigated AChE enzyme activity more than total bulb and aerial fractions with IC50 values of (0.06 ± 0.02, 0.58 ± 0.3, and 1.89 ± 0.42 µg/mL, respectively. Bioassay-guided acid-base fractionation confirmed superior BACE-1 inhibitory activity of the root fractions particularly, methylene chloride and ethyl acetate fractions with (IC50 values of 0.21 ± 0.60 and 0.01 ± 0.001 µg/mL), respectively. UPLC-MS analysis of ethyl acetate and methylene chloride fractions of C. miniata root led to the identification of eight phenolics and thirteen alkaloids, respectively. Molecular docking studies against BACE-1 protein revealed that lycorine di-hexoside, miniatine, and cliviaaline were the most promising hits. Further investigation of anti-AD potential of the aforementioned small molecules is required.

Recent Progresses in the Catalytic Stereoselective Dearomatization of Pyridines.

1,2- and 1,4-dihydropyridines and N-substituted 2-pyridones are very important structural motifs due to their synthetic versatility and vast presence in a variety of alkaloids and bioactive molecules. In this article, we gather and summarize the catalytic and stereoselective synthesis of partially hydrogenated pyridines and pyridones via the dearomative reactions of pyridine derivatives up to mid-2023. The material is fundamentally organized according to the type of reactivity (electrophilic/nucleophilic) of the pyridine nucleus. The material is further sub-divided taking into account the nucleophilic species when dealing with electrophilic pyridines and considering the reactivity manifold of pyridine derivatives behaving as nucleophiles at the nitrogen site. The latter more recent approach allows for an unconventional entry to chiral N-substituted 2- and 4-pyridones in non-racemic form.