Therapeutic potential of indole alkaloids in respiratory diseases: A comprehensive review

BackgroundIndole alkaloids are very promising for potential therapeutic purposes and appear to be particularly effective against respiratory diseases. Several experimental studies have been performed, both in vivo and in vitro, to evaluate the effectiveness of indole alkaloids for the management of respiratory disorders, including asthma, emphysema, tuberculosis, cancer, and pulmonary fibrosis.PurposeThe fundamental objective of this review was to summarize the in-depth therapeutic potential of indole alkaloids against various respiratory disorders.Study designIn addition to describing the therapeutic potential, this review also evaluates the toxicity of these alkaloids, which have been utilized for therapeutic benefits but have demonstrated toxic consequences. Some indole alkaloids, including scholaricine, 19-epischolaricine, vallesamine, and picrinine, which are derived from the plant Alstonia scholaris, have shown toxic effects in non-rodent models.MethodsThis review also discusses clinical studies exploring the therapeutic efficacy of indole alkaloids, which have confirmed the promising benefits observed in vivo and in vitro.ResultsThe indole alkaloidal compounds have shown efficacy in subjects with respiratory diseases.ConclusionThe available data established both preclinical and clinical studies confirm the potential of indole alkaloids to treat the respiratory disorders.     

Natural isoquinoline alkaloids: binding aspects to functional proteins,serum albumins,hemoglobin, and lysozyme

The putative anticancer alkaloids berberine, palmatine, jatrorrhizine, and sanguinarine are known to bind to nucleic acids. To develop them as potential drugs for therapeutic use, their binding affinity to functional proteins and mode of transport in the circulatory system need to be clearly understood. Towards this, many studies on their binding aspects to proteins have been reported and a considerable amount of data, mostly of biophysical nature, exists in the literature. The importance of these natural isoquinoline alkaloids and the recent literature on their interaction phenomena with functional proteins, serum albumins, hemoglobin, and lysozyme are presented in this review.     

Synthesis and structure-activity studies of antofine analogues as potential anticancer agents

Due to the profound cytotoxicities and interesting biochemical aspects, phenanthroindolizidine alkaloids have received an attention as potential therapeutic leads. To define the features of the molecule that are essential for cytotoxicity, we have synthesized and evaluated a series of phenanthroindolizidine alkaloid, antofine, analogues with different substituents on the phenanthrene ring. The systematic structure activity relationship studies elucidate the essential functional group requirement of phenanthrene ring, providing the basis for further development of phenanthroindolizidine alkaloids.     

The effects of biscoclaurine alkaloid cepharanthine on mammalian cells: implications for cancer, shock, and inflammatory diseases

The extract of Stephania cepharantha Hayata contains biscoclaurine alkaloids such as cepharanthine, which have been used widely in Japan for the treatment of patients with radiation-induced leukopenia, alopecia areata, exudative otitis media, and venomous snakebites. Many investigations have proven that the alkaloid cepharanthine exerts diverse pharmacological effects that include membrane-stabilizing, multidrug resistance-reversing, antitumor, apoptosis-inducing, anti-inflammatory, free radical scavenging, anti-HIV-1, antiallergic and immunomodulatory effects. The purpose of our review is to describe various therapeutic approaches using cepharanthine and their potential efficacy.     

Anticancer evaluation of structurally diverse Amaryllidaceae alkaloids and their synthetic derivatives

Plants of the Amaryllidaceae family have been under intense scrutiny for the presence of the specific metabolites responsible for the medicinal properties associated with them. The study began in 1877 with the isolation of alkaloid lycorine from Narcissus pseudonarcissus and since then more than 100 alkaloids, exhibiting diverse biological activities, have been isolated from the Amaryllidaceae plants. Based on the present scientific evidence, it is likely that isocarbostyril constituents of the Amaryllidaceae, such as narciclasine, pancratistatin and their congeners, are the most important metabolites responsible for the therapeutic benefits of these plant species in the folk medical treatment of cancer. Notably, Narcissus poeticus L., used by the ancient Greek physicians, is now known to contain about 0.12 g of narciclasine per kg of fresh bulbs. The focus of the present research work is the chemistry and biology of these compounds as specifically relevant to their potential use in medicine. In particular, the anticancer evaluation of lycorine, narciclasine as well as of other Amaryllidaceae alkaloids and their synthetic derivatives are presented in this paper. The structure–activity relationships among some groups of Amaryllidaceae alkaloids will be discussed.     

Characterisation of alkaloids from some Australian Stephania (Menispermaceae) species

Chemical investigations of some Stephania species native to Australia and reportedly employed by Aboriginal people as therapeutic agents, are described. The alkaloids from the forest vines Stephania bancroftii F.M. Bailey and S. aculeata F.M. Bailey (Menispermaceae) have been isolated and characterised. The major alkaloids in the tuber of the former species are (-)-tetrahydropalmatine and (-)-stephanine, whereas these are minor components in the leaves, from which a C-7 hydroxylated aporphine has been identified. The major tuber alkaloids in S. aculeata are (+)-laudanidine, and the morphinoid, (-)-amurine, whose absolute stereochemistry has been established by X-ray structural analysis of the methiodide derivative. No significant levels of alkaloids were detected in S. japonica. Complete and unambiguous 1H and 13C NMR data are presented for these alkaloids.     

RNA targeting by small molecules: Binding of protoberberine, benzophenanthridine and aristolochia alkaloids to various RNA structures

Studies on RNA targeting by small molecules to specifically control certain cellular functions is an area of remarkable current interest. For this purpose, a basic understanding of the molecular aspects of the interaction of small molecules with various RNA structures is essential. Alkaloids are a group of natural products with potential therapeutic utility, and very recently, their interaction with many RNA structures have been reported. Especially noteworthy are the protoberberines and aristolochia alkaloids distributed widely in many botanical families. Many of the alkaloids of these group exhibit excellent binding affinity to many RNA structures that may be exploited to develop RNA targeted therapeutics. This review attempts to present the current status on the understanding of the interaction of these alkaloids with various RNA structures, mainly highlighting the biophysical aspects.     

Manzamines

Manzamines are a unique class of β-carboline marine alkaloids with an unusual tetra- or pentacyclic system. These alkaloids have shown a variety of bioactivities against infectious diseases, cancer and inflammatory diseases. The greatest potential for the manzamine alkaloids appears to be against malaria, with improved potency relative to chloroquine and artemisinin. Over 80 manzamine-related alkaloids have been isolated from more than 16 species of marine sponges belonging to five families distributed from the Red Sea to Indonesia, which suggests a possible microbial origin for manzamine alkaloids. The current review summarizes marine literature, focusing on the biological activities of manzamines, the possible microbial origin of this class of compounds and the Red Sea as a possible source of manzamines from biosynthetic gene clusters of Red Sea microbes.     

Alterations of dorsal root potential in the course of transganglionic degenerative atrophy

Alterations in the dorsal root potential (DRP) which was evoked by stimulation of the common peroneal nerve of the rat, have been studied in the course of transganglionic degenerative atrophy (TDA) of primary sensory terminals in the upper dorsal horn. TDA was induced by perineural application of Vinca alkaloids around the sciatic nerve. In 9 to 30 days after this treatment, latency of DRP increased, whereas its amplitude and duration decreased. In this period, no C fibre response could be elicited. As a possible mechanism underlying the alterations of DRP, the functional consequences of atrophic changes of primary central afferent terminals are being discussed in terms of the close correlation between structure and function and the possible inferences of the electrophysiological reaction to the therapeutic application of Vinca alkaloids in the iontophoretic treatment of chronic intractable pain.     

Prospecting for Novel Plant-Derived Molecules of Rauvolfia serpentina as Inhibitors of Aldose Reductase,a Potent Drug Target for Diabetes and Its Complications

Aldose Reductase (AR) is implicated in the development of secondary complications of diabetes, providing an interesting target for therapeutic intervention. Extracts of Rauvolfia serpentina, a medicinal plant endemic to the Himalayan mountain range, have been known to be effective in alleviating diabetes and its complications. In this study, we aim to prospect for novel plant-derived inhibitors from R. serpentina and to understand structural basis of their interactions. An extensive library of R. serpentina molecules was compiled and computationally screened for inhibitory action against AR. The stability of complexes, with docked leads, was verified using molecular dynamics simulations. Two structurally distinct plant-derived leads were identified as inhibitors: indobine and indobinine. Further, using these two leads as templates, 16 more leads were identified through ligand-based screening of their structural analogs, from a small molecules database. Thus, we obtained plant-derived indole alkaloids, and their structural analogs, as potential AR inhibitors from a manually curated dataset of R. serpentina molecules. Indole alkaloids reported herein, as a novel structural class unreported hitherto, may provide better insights for designing potential AR inhibitors with improved efficacy and fewer side effects.     

Biotechnology and genetics of ergot alkaloids

Ergot alkaloids, i.e. ergoline-derived toxic metabolites, are produced by a wide range of fungi, predominantly by members of the grass-parasitizing family of the Clavicipitaceae. Naturally occurring alkaloids like the D-lysergic acid amides, produced by the "ergot fungus" Claviceps purpurea, have been used as medicinal agents for a long time. The pharmacological effects of the various ergot alkaloids and their derivatives are due to the structural similarity of the tetracyclic ring system to neurotransmitters such as noradrenaline, dopamine or serotonin. In addition to "classical" indications, e.g. migraine or blood pressure regulation, there is a wide spectrum of potential new applications of this interesting group of compounds. The biotechnology of ergot alkaloids has a long tradition, and efficient parasitic and submerse production processes have been developed; the biochemistry of the pathway and the physiology of production have been worked out in detail. The recent identification of a cluster of genes involved in ergot alkaloid biosynthesis in C. purpurea and the availability of molecular genetic techniques allow the development of strategies for rational drug design of ergoline-related drugs by enzyme engineering and by biocombinatorial approaches.     

Pyridine alkaloids with activity in the central nervous system

This review discusses all pyridine alkaloids with CNS activity, their therapeutic potential, and the interesting array of sources whence they originate.     

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.     

The ergot alkaloid gene cluster: Functional analyses and evolutionary aspects

Ergot alkaloids and their derivatives have been traditionally used as therapeutic agents in migraine, blood pressure regulation and help in childbirth and abortion. Their production in submerse culture is a long established biotechnological process. Ergot alkaloids are produced mainly by members of the genus Claviceps, with Claviceps purpurea as best investigated species concerning the biochemistry of ergot alkaloid synthesis (EAS). Genes encoding enzymes involved in EAS have been shown to be clustered; functional analyses of EAS cluster genes have allowed to assign specific functions to several gene products. Various Claviceps species differ with respect to their host specificity and their alkaloid content; comparison of the ergot alkaloid clusters in these species (and of clavine alkaloid clusters in other genera) yields interesting insights into the evolution of cluster structure. This review focuses on recently published and also yet unpublished data on the structure and evolution of the EAS gene cluster and on the function and regulation of cluster genes. These analyses have also significant biotechnological implications: the characterization of non-ribosomal peptide synthetases (NRPS) involved in the synthesis of the peptide moiety of ergopeptines opened interesting perspectives for the synthesis of ergot alkaloids; on the other hand, defined mutants could be generated producing interesting intermediates or only single peptide alkaloids (instead of the alkaloid mixtures usually produced by industrial strains).     

In vitro and in vivo cancer cell apoptosis triggered by competitive binding of Cinchona alkaloids to the RING domain of TRAF6

TRAF6 is highly expressed in many tumors and plays an important role in the immune system. The aim of this study is to confirm anti-tumor activities of all naturally occurring Cinchona alkaloids that have been screened using computational docking program, and to validate the accuracy and specificity of the RING domain of TRAF6 as a potential anti-tumor target, and to explore their effect on the immune system. Results reported herein would demonstrate that Cinchona alkaloids could induce apoptosis in HeLa cells, inhibit the ubiquitination and phosphorylation of both AKT and TAK1, and up-regulate the ratio of Bax/Bcl-2. In addition, these compounds could induce apoptosis in vivo, and increase the secretion of TNF-α, IFN-γ, and IgG, while not significantly impacting the ratio of CD4⁺T/CD8⁺T. These investigations suggest that the RING domain of TRAF6 could serve as a de novo biological target for therapeutic treatment in cancers.     

Bioactive molecules from amphibian skin: their biological activities with reference to therapeutic potentials for possible drug development

The amphibian skin contains various bioactive molecules (peptides, proteins, steroids, alkaloids, opiods) that possess potent therapeutic activities like antibacterial, antifungal, antiprotozoal, antidiabetic, antineoplastic, analgesic and sleep inducing properties. Research on amphibian skin derived biomolecules can provide potential clue towards newer drug development to combat various pathophysiological conditions. An overview on the bioactive molecules of various amphibian skins has been discussed.     

Interaction of the putative anticancer alkaloid chelerythrine with nucleic acids: biophysical perspectives

Alkaloids represent an important group of molecules that have immense pharmacological potential. Benzophenanthridine alkaloids are one such class of alkaloids known for their myriad pharmacological activities that include potential anticancer activities. Chelerythrine is a premier member of the benzophenanthridine family of the isoquinoline group. This alkaloid is endowed with excellent medicinal properties and exhibits antibacterial, antimicrobial and anti-inflammatory properties. The molecular basis of its therapeutic activity is considered due to its nucleic acid binding capabilities. This review focuses on consolidating the current status on the nucleic acid binding properties of chelerythrine that is essential for the rational design and development of this alkaloid as a potential drug. This work reviews the interaction of chelerythrine with different natural and synthetic nucleic acids like double- and single-stranded DNAs, heat-denatured DNA, quadruplex DNA, double- and single-stranded RNA, tRNA and triplex and quadruplex RNA. The review emphasizes on the mode, specificity, conformational aspects and energetics of the binding that is particularly helpful for developing nucleic acid targeted therapeutics. The fundamental results discussed in this review will greatly benefit drug development for many diseases and serve as a database for the design of futuristic benzophenanthridine-based therapeutics.     

Hidden costs to an invasive intraguild predator from chemically defended native prey

Studies of invasive species tend to concentrate on the reasons for their success, rather than on the potential costs that they face. Invasive predators are potentially vulnerable to chemical defences of native prey that they have not previously encountered, and evolved to tolerate, within their natural range. While novel chemical defences have been cited as a factor facilitating invasion by exotic prey, the potential costs of chemical novelty to invasive predators have been ignored or remained hidden. We here consider one such example. Although a dominant intraguild predator in interactions with native ladybird beetles, the invasive ladybird Harmonia axyridis finds the defensive alkaloids of certain native ladybirds either distasteful or toxic, although laboratory and field evidence suggests it readily attacks these prey; these natives appear to possess novel alkaloids not previously encountered by H. axyridis . This effect has hitherto remained hidden, due to the methodological approaches used in earlier studies.     

Structure,synthesis and biological properties of the pentacyclic guanidinium alkaloids

The pentacyclic guanidinium alkaloids (PGAs) are a family of marine natural products that possess a polycyclic guanidine-containing core and a long alkyl chain tethered spermidine-derived tail that is rarely observed in other natural products. These natural products exhibit potent activities on a wide range of organisms and therefore have attracted the attention of many synthetic chemists; however, the structure-activity relationships and mechanisms of action of PGAs remain largely elusive. Herein we summarize the structure, synthesis, toxicity and mechanisms of action of PGAs and highlight their potential as chemical probes and/or therapeutic leads.