Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective

Secondary metabolites, at least the major ones present in a plant, apparently function as defence (against herbivores, microbes, viruses or competing plants) and signal compounds (to attract pollinating or seed dispersing animals). They are thus important for the plant's survival and reproductive fitness. Secondary metabolites therefore represent adaptive characters that have been subjected to natural selection during evolution. Molecular phylogenies of the Fabaceae, Solanaceae and Lamiaceae were reconstructed and employed as a framework to map and to interpret the distribution of some major defence compounds that are typical for the respective plant families; quinolizidine alkaloids and non-protein amino acids for legumes; tropane and steroidal alkaloids for Solanaceae, and iridoids and essential oils for labiates. The distribution of the respective compounds appears to be almost mutually exclusive in the families studied, implying a strong phylogenetic and ecological component. However, on a closer look, remarkable exceptions can be observed, in that certain metabolites are absent (or present) in a given taxon, although all the neighbouring and ancestral taxa express (or do not express, respectively) the particular trait. It is argued that these patterns might reflect differential expression of the corresponding genes that have evolved earlier in plant evolution. The inconsistent secondary metabolite profiles mean that the systematic value of chemical characters becomes a matter of interpretation in the same way as traditional morphological markers. Thus, the distribution of secondary metabolites has some value for taxonomy but their occurrence apparently reflects adaptations and particular life strategies embedded in a given phylogenetic framework.     

Synthesis and evaluation of the anti-proliferative and NF-κB activities of a library of simplified tylophorine analogs

Tylophorine and many related phenanthropiperidine alkaloids are extraordinarily potent anti-proliferative agents. Despite their impressive anti-cancer activity, clinical development of these alkaloids has been hampered by their poor solubility and neurological side effects. Although it has been suggested that developing polar phenanthropiperidines will mitigate these undesired properties, the lack of practical methods for the synthesis of such analogues has limited this effort. Here, we present a concise synthetic approach to N-substituted phenanthropiperidines, which enabled a systematic investigation of structure-activity relationships at an underexplored region of the tylophorine scaffold. This work suggests that ring E of tylophorine is essential for the anti-proliferative activity of the 6,7,10,11-tetramethoxy-1,2,3,4-tetrahydrodibenzo[f,h]isoquinoline core scaffold.     

Secondary metabolites and the higher classification of angiosperms

The restricted distributions of some classes of secondary metabolites in the angiosperms make them valuable taxonomic characters in assessing systematic relationships at higher levels of classification. Yet, for several reasons, secondary metabolites have not, until recently, been widely used as taxonomic characters above the family level. In this paper, the distributions of a number of classes of secondary compounds are discussed with reference to four recently published systems of higher angiosperm classification: Cronquist's of 1981, Dahlgren's of 1980, Takhtajan's of 1980 and Thome's of 1981. Some of the problems faced in choosing and using secondary metabolite data for systematic purposes (including the effects of our increasing understanding of their functional significance) are covered as well. Among the classes of secondary compounds treated here, benzylisoquinoline alkaloids, iridoids and be–talains are shown to be the most important systematic markers used at present at higher levels of classification, although glucosinolates, polyacetylenes and some other types of alkaloids are also demonstrated to be valuable criteria for making taxonomic judgments above the family rank. In addition, certain terpenoids, flavonoids, phenolics, cyanogenic glycosides and non–protein amino acids are illustrated to be of systematic use in particular cases.     

02428×合系35 的RIL群体糙米总黄酮与总生物碱含量的遗传分析

测定了水稻02428与合系35杂交培育的222个RIL（重组自交系）及其亲本的发芽糙米和糙米总黄酮和生物碱含量,对其进行遗传分析和探讨了发芽糙米和糙米中总黄酮、生物碱的含量变化。结果表明,RIL群体发芽糙米和糙米中总黄酮、生物碱呈现广泛的遗传变异,糙米总黄酮含量略高于发芽糙米,但两者均呈正态分布,类似于数量性状的分布特征。RIL群体发芽糙米生物碱含量是糙米的1.5倍,且两者呈偏态分布;为功能水稻的遗传及品种选育提供一定的理论依据。     

Use of the metabolic grid to explain the metabolism of quinolizidine alkaloids in Leguminosae

Evidence from feeding experiments with lysine-[2-¹⁴C] and from metabolism experiments published previously suggest the operation of a gridlike conversion of quinolizidine alkaloids in Leguminosae. Using these results and the taxonomical distribution of alkaloids a metabolic grid was devised to explain the conversion of lysine into lupin alkaloids and their interconversions.     

Distribution of Benzylisoquinolines in Magnoliidae and Other Taxa

Based on the analysis of benzylisoquinoline alkaloids of 323 samples in 11 families, 50 genera and 181 species of the Chinese flora discussed in this paper are the biogenesis, evolution, distribution pattern and botanical sources as well as the pharmacological action of this specific category of alkaloids. Benzylisoquinoline alkaloids are found mainly in Magnoliidae, in which aporphines, bisbenzylisoquinolines and protoberberines are the three major types of the alkaloids. More specifically, aporphines appeare more concentrated in primitive woody plants such as the Annonaceae, while bisbenzylisoquinolines are especially common in the Menispermaceae, Thalictrum (the Ranunculaceae) and Berberis (the Berberidaceae). As to protoberberines, the quaternary ones occur mainly in the families Ranunculaceae and Berberidaceae, whereas the tertiary ones mainly in the relatively advanced families Menispermaceae and Papaveraceae within Magnoliidae. As a whole, a general rule can be drawn that the simpler the chemical structure of the benzylisoquinolines is, the more widely they are distributed in primitive groups; more specific ones only have a limited distribution in more advanced groups or even within one family or one to several genera. This general pattern of distribution of benzylisoquinoline alkaloids in plants may be of value as a taxonomic criterion for plant systematics. Furthermore, this group of alkaloids covers the gamut of pharmacologic responses, such as the antibacterial effect and the effect to cardiovascular and nervous systems, and consequently the correlation between benzylisoquinoline alkaloids and their pharmacologicactivities within Magnoliidae may worthily be applied for the finding of new drugs.     

Alkaloids of Toddalia asiatica (Rutaceae)

Phytochemical investigation of the alkaloidal extract of the roots of Toddalia asiatica led to the isolation of a new seco-benzophenanthridine alkaloid (1) and twelve known alkaloids (2–13). The new structure was elucidated by means of spectroscopic analysis, and the known alkaloids were identified by comparison with the literature. Among these alkaloids, 1 and 5–7 were reported from the genus Toddalia for the first time. The distribution of the isolated alkaloids at genus/family level was presented via network analysis and their chemotaxonomic significance was also discussed.     

The Spatial Distribution of Alkaloids in Psychotria prunifolia (Kunth) Steyerm and Palicourea coriacea (Cham.) K. Schum Leaves Analysed by Desorption Electrospray Ionisation Mass Spectrometry Imaging

Introduction

Species of the genera Psychotria and Palicourea are sources of indole alkaloids, however, the distribution of alkaloids within the plants is not known. Analysing the spatial distribution using desorption electrospray ionisation mass spectrometry imaging (DESI‐MSI) has become attractive due to its simplicity and high selectivity compared to traditional histochemical techniques.

Objectives

To apply DESI‐MSI to visualise the alkaloid distribution on the leaf surface of Psychotria prunifolia and Palicourea coriacea and to compare the distributions with HPLC–MS and histochemical analyses.

Methodology

Based upon previous structure elucidation studies, four alkaloids targeted in this study were identified using high resolution mass spectrometry by direct infusion of plant extracts, and their distributions were imaged by DESI‐MSI via tissue imprints on a porous Teflon surface. Relative quantitation of the four alkaloids was obtained by HPLC–MS/MS analysis performed using multiple‐reaction monitoring (MRM) mode on a triple quadrupole mass spectrometer.

Results

Alkaloids showed distinct distributions on the leaf surfaces. Prunifoleine was mainly present in the midrib, while 10‐hydroxyisodeppeaninol was concentrated close to the petiole; a uniform distribution of 10‐hydroxyantirhine was observed in the whole leaf of Psychotria prunifolia. The imprinted image from the Palicourea coriacea leaf also showed a homogeneous distribution of calycanthine throughout the leaf surface.

Conclusion

Different distributions were found for three alkaloids in Psychotria prunifolia, and the distributions found by MSI were in complete accordance with HPLC–MS analysis and histochemical results. The DESI‐MSI technique was therefore demonstrated to provide reliable information about the spatial distribution of metabolites in plants. Copyright © 2017 John Wiley & Sons, Ltd.     

The genus <Emphasis Type="Italic">Lindera</Emphasis>: a source of structurally diverse molecules having pharmacological significance

Lindera plants not only have good ornamental and economic uses but also have great medicinal and therapeutic values. The genus Lindera consists of approximately 100 species that are widely distributed in tropical and subtropical areas throughout the world. This extensive geographical distribution allows Lindera plants to produce diverse secondary metabolites having novel structures. Phytochemical investigations have shown that Lindera plants produce 341 constituents, including sesquiterpenoids, alkaloids, butanolides, lucidones, flavonoids, and phenylpropanoids. Moreover, some Lindera plants show significant chemotaxonomic reference under family Lauraceae and tribe Litseae. Although Lindera plants have various pharmacological and biological properties, their anticancer, antihypertensive, anti-inflammatory, and analgesic properties have been focused in many studies. Butanolides and lucidones have shown great potential in developing anticancer agents while aporphine alkaloids have shown great potential in developing antiarthritic and antinociceptive agents. However, these compounds need to be assessed further by performing in-depth and systematic research.     

02428×合系35的RIL群体糙米总黄酮与总生物碱含量的遗传分析

测定了水稻02428与合系35杂交培育的222个RIL(重组自交系)及其亲本的发芽糙米和糙米总黄酮和生物碱含量,对其进行遗传分析及探讨了发芽糙米和糙米中总黄酮、生物碱的含量变化.结果表明,RIL群体发芽糙米和糙米中总黄酮、生物碱呈现广泛的遗传变异,糙米总黄酮含量略高于发芽糙米,但两者均呈正态分布,类似于性状的分布特征.RIL群体发芽糙米生物碱含量是糙米的1.5倍,且两者呈偏态分布;为功能水稻的遗传及品种选育提供了一定的理论依据.     

Sequestration of pyridine alkaloids anabasine and nicotine from Nicotiana (Solanaceae) by Orobanche ramosa (Orobanchaceae)

Plants of the root holoparasite Orobanche ramosa L. and four of its potential host species, Nicotiana glauca Graham, Nicotiana rustica L., Nicotiana sylvestris Speg. & S.Comes, and Nicotiana tabacum L., grown in the greenhouse in Kiel/Germany, were analyzed for their contents of pyridine alkaloids anabasine (1) and nicotine (2). All investigated samples contained both alkaloids in different amounts. The distribution of the alkaloids in the various plant organs of Nicotiana differed significantly between the species. The alkaloid contents of the Orobanche samples relative to the alkaloid contents of the roots of the respective host plants varied between 3.47 ± 1.08 and 28.8 ± 37.5%. Orobanche plants drain water and crucial nutrients from their hosts; also, some examples for the sequestration of specialized natural products have been reported. O. ramosa is not able to synthesize pyridine alkaloids anabasine (1) and nicotine (2) itself; therefore, the present study proves the sequestration of pyridine alkaloids by O. ramosa from the four investigated Nicotiana host species.     

Quaternary protoberberine alkaloids

This contribution reviews some general aspects of the quaternary iminium protoberberine alkaloids. The alkaloids represent a very extensive group of secondary metabolites with diverse structures, distribution in nature, and biological effects. The quaternary protoberberine alkaloids (QPA), derived from the 5,6-dihydrodibenzo[a,g]quinolizinium system, belong to a large class of isoquinoline alkaloids. Following a general introduction, the plant sources of QPA, their biosynthesis, and procedures for their isolation are discussed. Analytical methods and spectral data are summarized with emphasis on NMR spectroscopy. The reactivity of QPA is characterized by the sensitivity of the iminium bond CN(+) to nucleophilic attack. The addition of various nucleophiles to the protoberberine skeleton is discussed. An extended discussion of the principal chemical reactivity is included since this governs interactions with biological targets. Quaternary protoberberine alkaloids and some related compounds exhibit considerable biological activities. Recently reported structural studies indicate that the QPA interact with nucleic acids predominantly as intercalators or minor groove binders. Currently, investigations in many laboratories worldwide are focused on the antibacterial and antimalarial activity, cytotoxicity, and potential genotoxicity of QPA.     

Geranylated carbazole alkaloids with potential neuroprotective activities from the stems and leaves of Clausena lansium

Clausena lansium (Lour.) Skeels is an evergreen small tree or shrub with great economic value, which belongs to the genus Clausena of the Rutaceae family. C. lansium is indigenous to Southern China, while currently widely cultivated in subtropical and tropical regions not only for the nutritional value and pharmacological uses of its fruits but also as a medicinal and ornamental plant. In this study, a systematic phytochemical study on the stems and leaves of C. lansium caused the separation and identification of two new geranylated carbazole alkaloids, clauselansiumines A (1) and B (2), as well as 10 known geranylated carbazole alkaloids (3–12). The chemical structures of these isolated geranylated carbazole alkaloids (1–12) were unambiguously determined based on comprehensive spectral data analyses. All these isolated geranylated carbazole alkaloids were tested for their neuroprotective effects against 6-hydroxydopamine induced cell death in human neuroblastoma SH-SY5Y cells in vitro. Compounds 1–12 displayed remarkable neuroprotective effects holding the EC₅₀ values ranging from 0.48 ± 0.04 to 12.36 ± 0.16 μM. These research results disclosed that the separation and purification of these geranylated carbazole alkaloids possessing remarkable neuroprotective effects separated from C. lansium could be extremely important to the discovery of new agents for the treatment and prevention for Parkinson's disease.     

切叶蚁亚科蚂蚁的防御性生物碱

蚂蚁(蚁科)有显著的群居特性,个体间分工明确,并具有复杂的合作策略,以保护巢穴不受捕食者、病原微生物、蚂蚁竞争者的侵害,以及捕食猎物等.切叶蚁亚科是蚁科的最大类群,共有147个现生属,主要通过喷洒富含生物碱的毒液分泌物进行防御和捕猎.本文综述了该亚科防御性生物碱的组分及属种分布特征,其结构类型包括哌啶、吡啶、吡咯、吲哚...     

Chemometric analysis applied to a chemophenetics approach in Simaroubaceae family: The relevance of alkaloids and quassinoids

Simaroubaceae family belongs to the order Sapindales, which in turn is part of Eurosides II (APG IV). It consists of 23 genera: Ailanthus; Amaroria; Brucea; Castela; Eurycoma; Gymnostemon; Hannoa; Holacantha; Homalolepsis; Iridosma; Laumoniera; Leitneria; Nothospondias; Odyendeya; Perriera; Picrasma; Picrolemma; Pierreodendron; Quassia; Samadera; Simaba; Simarouba; Soulamea. Over the years, the classification of Simaroubaceae has changed and there is still a lot to evolve in this direction since there are still not many studies on some of its genera. In this sense, the present work discusses the chemistry of Simaroubaceae through the micromolecular chemical data, evolutionary indexes and chemometric analysis in order to assess affinities between its genera. The chemistry of this family is diverse and includes quassinoids, alkaloids, triterpenes, flavonoids, simple phenolics, coumarins, lignans and quinones. In addition to presenting specificity, quassinoids and alkaloids are prevalent among the substances already identified in the family and can be considered the chemical markers of it. Quassionoids are degraded triterpenes and can be classified as c25, c22, c20, c 19 and c18; c20 being the most common type in the family. The alkaloids already isolated in Simaroubaceae are predominantly beta-carboline and canthinone, both originating from the amino acid tryptophan. The evolutionary indexes calculated for the chemical markers showed great variation between the genera of Simaroubaceae and showed no correlation among them. The chemometric analysis positioned Simaroubaceae close to Rutaceae within the order Sapindales and, among the genera, alkaloids and quassinoids were very important for their distribution in Simaroubaceae considering the evolutionary proximity, corroborating their selection as chemical markers.     

Crinum alkaloids: their chemistry and biology

The current staus of research of free and glycosylated alkaloids occuring in members of the genus Crinum is reviewed. The distribution, isolation, spectral properties, structural properties, inter conventions and biological acitivities of these alkaloids are presented.     

Stimulation of topoisomerase II-mediated DNA cleavage by three DNA-intercalating plant alkaloids: cryptolepine, matadine, and serpentine.

Cryptolepine, matadine, and serpentine are three indoloquinoline alkaloids isolated from the roots of African plants: Cryptolepis sanguinolenta, Strychnos gossweileri, and Rauwolfia serpentina, respectively. For a long time, these alkaloids have been used in African folk medicine in the form of plant extracts for the treatment of multiple diseases, in particular as antimalarial drugs. To date, the molecular basis for their diverse biological effects remains poorly understood. To elucidate their mechanism of action, we studied their interaction with DNA and their effects on topoisomerase II. The strength and mode of binding to DNA of the three alkaloids were investigated by spectroscopy. The alkaloids bind tightly to DNA and behave as typical intercalating agents. All three compounds stabilize the topoisomerase II-DNA covalent complex and stimulate the cutting of DNA by topoisomerase II. The poisoning effect is more pronounced with cryptolepine than with matadine and serpentine, but none of the drugs exhibit a preference for cutting at a specific base. Cryptolepine which binds 10-fold more tightly to DNA than the two related alkaloids proves to be much more cytotoxic toward B16 melanoma cells than matadine and serpentine. The cellular consequences of the inhibition of topoisomerase II by cryptolepine were investigated using the HL60 leukemia cell line. The flow cytometry analysis shows that the drug alters the cell cycle distribution, but no sign of drug-induced apoptosis was detected when evaluating the internucleosomal fragmentation of DNA in cells. Cryptolepine-treated cells probably die via necrosis rather than via apoptosis. The results provide evidence that DNA and topoisomerase II are the primary targets of cryptolepine, matadine, and serpentine.     

Two Delphinium ramosum chemotypes,their biogeographical distribution and potential toxicity

Larkspurs (Delphinium, Ranunculaceae) are poisonous plants found on rangelands throughout Western North America. Two main structural groups of norditerpene alkaloids, the N-(methylsuccinimido) anthranoyllycoctonine type (MSAL-type) and the non-MSAL type, are responsible for larkspur-induced poisoning. Information on the alkaloid composition is lacking for a number of Delphinium species, including D. ramosum. Delphinium ramosum grows throughout parts of Colorado and northern New Mexico. The objective of this study was to profile the alkaloid composition of D. ramosum throughout its geographical distribution using both field and herbarium specimens. Two alkaloid profiles were identified, one that contained significantly greater concentrations of the MSAL-type alkaloids than the other. Plants containing each respective alkaloid profile were unique in their geographical distribution. Populations of these two chemotypes will likely differ in their toxic potential and consequently pose different risks of poisoning when grazed by livestock species. This information has important implications in grazing management decisions on D. ramosum-infested rangelands and demonstrates that botanical classification alone is not an adequate indicator of relative risk of toxicity.     

Cellular distribution of alkaloids and their translocation via phloem and xylem: the importance of compartment pH

The physico‐chemical background of alkaloid allocation within plants is outlined and discussed exemplarily for pyrrolizidine alkaloids (PAs) and nicotine. The trigger for this discourse is the finding that, for example, PAs, which are taken up from the soil, are translocated in the xylem, whereas – when genuinely present in plants – they are allocated as N‐oxides via phloem. Special emphasis is put on the impact of different pH values in certain compartments, as this entails significant changes in the relative lipophilic character of alkaloids: tertiary alkaloids diffuse readily through biomembranes, while the corresponding protonated alkaloids are retained in acidic compartments, i.e. vacuoles or xylem. Therefore, this phenomenon, well known as the ‘ion trap mechanism’, is also relevant for long‐distance transport of alkaloids. Any efficient allocation of typical tertiary alkaloids within the phloem can thus be excluded. In contrast, due to their strongly increased hydrophilic properties, alkaloid‐N‐oxides or quarternary alkaloids cannot diffuse through biomembranes and, consequently, would be retained in the acidic xylem during translocation. The major aim of this paper is to sharpen the mind for the chemical peculiarities of alkaloids and to consider them adequately in forthcoming investigations on allocation of alkaloids.     

The alkaloid profiles of Sophora nuttalliana and Sophora stenophylla

Sophora is a diverse genus in the family Fabaceae, comprised of herbs, shrubs, and trees that occurs throughout the world, primarily in the northern hemisphere. Species of Sophora are known to contain quinolizidine alkaloids that are toxic and potentially teratogenic. Two perennial herbaceous species occur in North America, Sophora stenophylla and Sophora nuttalliana. The quinolizidine alkaloid composition of these two species was investigated throughout their geographical distribution using field collections and herbarium specimens. Both species contain quinolizidine alkaloids, and S. nuttalliana contains the teratogen anagyrine. Lastly, neither species contains the neurotoxin swainsonine as implied by the common name “white loco” for S. nuttalliana.