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Journal of Medicinal Chemistry Aug 2023Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new...
Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new ferroptosis inducers proceeds rather slowly, with only a few small molecules identified. Herein, we report our discovery of marine alkaloid lepadins E and H as a new class of ferroptosis inducers. Our in vitro studies show that lepadins E and H exhibit significant cytotoxicity, promote p53 expression, increase ROS production and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate ACSL4 expression, all of which consistently support induction of ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Our animal model study of lepadin H confirms its in vivo antitumor efficacy with negligible toxicity to normal organs. This work elucidates the mode of action of lepadins (E and H) and verifies their in vivo efficacy as a new class of ferroptosis inducers for anticancer therapy with translational potential.
Topics: Animals; Alkaloids; Antineoplastic Agents; Ferroptosis; Neoplasms; Tumor Suppressor Protein p53
PubMed: 37578947
DOI: 10.1021/acs.jmedchem.3c00659 -
Toxins Jul 2023Venoms produced by arthropods act as chemical weapons to paralyze prey or deter competitors. The utilization of venom is an essential feature in the biology and ecology... (Review)
Review
Venoms produced by arthropods act as chemical weapons to paralyze prey or deter competitors. The utilization of venom is an essential feature in the biology and ecology of venomous arthropods. fire ants (Hymenoptera: Formicidae) are medically important venomous ants. They have acquired different patterns of venom use to maximize their competitive advantages rendered by the venom when facing different challenges. The major components of fire ant venom are piperidine alkaloids, which have strong insecticidal and antibiotic activities. The alkaloids protect fire ants from pathogens over the course of their lives and can be used to defend them from predators and competitors. They are also utilized by some of the fire ants' natural enemies, such as phorid flies to locate host ants. Collectively, these ants' diverse alkaloid compositions and functions have ecological significance for their survival, successful invasion, and rapid range expansion. The venom alkaloids with powerful biological activities may have played an important role in shaping the assembly of communities in both native and introduced ranges.
Topics: Animals; Ant Venoms; Arthropod Venoms; Ants; Diptera; Alkaloids
PubMed: 37505709
DOI: 10.3390/toxins15070439 -
Toxins Feb 2022Plants are the cradle of the traditional medicine system, assuaging human or animal diseases, and promoting health for thousands of years. However, many plant-derived... (Review)
Review
Plants are the cradle of the traditional medicine system, assuaging human or animal diseases, and promoting health for thousands of years. However, many plant-derived medicines contain toxic alkaloids of varying degrees of toxicity that pose a direct or indirect threat to human and animal health through accidental ingestion, misuse of plant materials, or through the food chain. Thus, rapid, easy, and sensitive methods are needed to effectively screen these toxic alkaloids to guarantee the safety of plant-derived medicines. Antibodies, due to their inherent specificity and high affinity, have been used as a variety of analytical tools and techniques. This review describes the antigen synthesis and antibody preparation of the common toxic alkaloids in plant-derived medicines and discusses the advances of antibody-based immunoassays in the screening and detection of toxic alkaloids in plants or other related matrices. Finally, the limitations and prospects of immunoassays for toxic alkaloids are discussed.
Topics: Alkaloids; Animals; Immunoassay; Medicine, Traditional; Plants, Toxic
PubMed: 35324662
DOI: 10.3390/toxins14030165 -
Phytomedicine : International Journal... Jan 2023Viral-borne diseases are amongst the oldest diseases known to mankind. They are responsible for some of the most ravaging effects wrought on human health and well-being.... (Review)
Review
BACKGROUND
Viral-borne diseases are amongst the oldest diseases known to mankind. They are responsible for some of the most ravaging effects wrought on human health and well-being. The use of plants against these ailments is entrenched in both traditional and secular medicine around the globe. Their natural abundance and chemical diversity have also boosted their appeal in drug discovery.
AIM
The plant family Amaryllidaceae is distinguished for its alkaloid principles, some of which are of considerable interest in the clinical arena. This account is the outcome of a literature review undertaken to establish the applicability of these substances as antiviral agents.
METHODS
The survey utilized the search engines Google Scholar, PubMed, SciFinder, Scopus and Web of Science engaging the word 'antiviral' in conjunction with 'Amaryllidaceae' and 'Amaryllidaceae alkaloid'. The search returned over five hundred hits, of which around eighty were of relevance to the theme of the text.
RESULTS
Over eighty isoquinoline alkaloids have been screened against nearly fifty pathogens from fourteen viral families, the majority of which were RNA viruses. Potent activities were reported in some instances, such as that of trans-dihydronarciclasine against Yellow fever virus (IC 0.003 μg/ml), with minimal effects being manifested on host cells. There were also promising results obtained from in vivo studies, in most cases without lethal effects on test subjects. Structure-activity relationship studies afforded useful insight to the antiviral pharmacophore, with the phenanthridone alkaloid nucleus shown to be the most enabling. Although the mechanistic basis to these activities pertained mostly to inhibition of DNA, RNA and protein synthesis, evidence was also forthcoming about the inhibitory action of some of the alkaloids against viral neuraminidase, protease and reverse transcriptase. In silico methods of analysis have offered further perspectives of how some of the alkaloids interact at the active sites of their targets.
CONCLUSION
The Amaryllidaceae offers a viable platform for plant-based antiviral drug discovery. Its cause is strengthened not only by its wide proliferation and exploitation of its members in alternative forms of medicine, but also by its rich chemical diversity which has already spawned useful antiviral drug leads.
Topics: Humans; Amaryllidaceae; Amaryllidaceae Alkaloids; Antiviral Agents; Alkaloids; Plant Extracts
PubMed: 36240608
DOI: 10.1016/j.phymed.2022.154480 -
Nature Chemistry Jul 2020The fungal-derived bicyclo[2.2.2]diazaoctane alkaloids are of interest to the scientific community for their potent and varied biological activities. Within this large...
The fungal-derived bicyclo[2.2.2]diazaoctane alkaloids are of interest to the scientific community for their potent and varied biological activities. Within this large and diverse family of natural products, the insecticidal metabolite (+)-brevianamide A is particularly noteworthy for its synthetic intractability and inexplicable biogenesis. Despite five decades of research, this alkaloid has remained an elusive target for chemical synthesis due to insurmountable issues of reactivity and selectivity associated with all previously explored strategies. We herein report the chemical synthesis of (+)-brevianamide A (seven steps, 7.2% overall yield, 750 mg scale), which involves a bioinspired cascade transformation of the linearly fused (-)-dehydrobrevianamide E into the topologically complex bridged-spiro-fused structure of (+)-brevianamide A.
Topics: Alkaloids; Biological Products; Chemistry Techniques, Synthetic; Cyclization; Molecular Structure; Penicillium; Piperazines; Spiro Compounds; Stereoisomerism
PubMed: 32284576
DOI: 10.1038/s41557-020-0442-3 -
Natural Product Reports May 2023Covering: up to July 2022Stemmadenine alkaloids are a restrictive sub-group of monoterpene indole alkaloids, represented by two congeners: stemmadenine and vallesamine.... (Review)
Review
Covering: up to July 2022Stemmadenine alkaloids are a restrictive sub-group of monoterpene indole alkaloids, represented by two congeners: stemmadenine and vallesamine. Their skeleton is defined by the cleavage of the C-3-C-7 bond of the group's pentacyclic scaffold in monoterpene indole alkaloids. The parent alkaloid stemmadenine acts as a key intermediate in the biosynthesis of several major monoterpene indole alkaloid families, including regular alkaloids, alkaloids, and alkaloids. In this review, a complete coverage of the stemmadenine alkaloids, from the early reports till the present day at 2022, are presented, and their diverse biological activities are briefly described. Moreover, the biosynthetic proposal for stemmadenine and the proposed biogenetic conversion of stemmadenine-type alkaloids into vallesamine-type congeners are discussed in detail. Moreover, the successful synthetic strategies to access the strained stemmadenine scaffolds are fully reviewed.
Topics: Humans; Indole Alkaloids; Alkaloids; Ibogaine; Monoterpenes
PubMed: 36728407
DOI: 10.1039/d2np00052k -
Naunyn-Schmiedeberg's Archives of... Feb 2023Cryptolepine (1,5-methyl-10H-indolo[3,2-b]quinoline), an indoloquinoline alkaloid, found in the roots of Cryptolepis sanguinolenta (Lindl.) Schltr (family:... (Review)
Review
Cryptolepine (1,5-methyl-10H-indolo[3,2-b]quinoline), an indoloquinoline alkaloid, found in the roots of Cryptolepis sanguinolenta (Lindl.) Schltr (family: Periplocaceae), is associated with the suppression of cancer and protozoal infections. Cryptolepine also exhibits anti-bacterial, anti-fungal, anti-hyperglycemic, antidiabetic, anti-inflammatory, anti-hypotensive, antipyretic, and antimuscarinic properties. This review of the latest research data can be exploited to create a basis for the discovery of new cryptolepine-based drugs and their analogues in the near future. PubMed, Scopus, and Google Scholar databases were searched to select and collect data from the existing literature on cryptolepine and their pharmacological properties. Several in vitro studies have demonstrated the potential of cryptolepine A as an anticancer and antimalarial molecule, which is achieved through inhibiting DNA synthesis and topoisomerase II. This review summarizes the recent developments of cryptolepine pharmacological properties and functional mechanisms, providing information for future research on this natural product.
Topics: Indole Alkaloids; Quinolines; Alkaloids; Antimalarials
PubMed: 36251044
DOI: 10.1007/s00210-022-02302-7 -
Natural Product Reports Dec 2022Covering: 2009 to 2022The alkaloids, which are found in plant species from the family Stemonaceae, represent a tremendously large and structurally-diverse family of... (Review)
Review
Covering: 2009 to 2022The alkaloids, which are found in plant species from the family Stemonaceae, represent a tremendously large and structurally-diverse family of natural products. This review presents and discusses a selection of case studies, grouped by alkaloid class, that showcase the key strategies and overall progress that has been made in the synthesis of alkaloids and related compounds since 2009. Structural reassignments that have been reported over this period are also identified where necessary.
Topics: Stemonaceae; Alkaloids; Molecular Structure
PubMed: 36218078
DOI: 10.1039/d2np00058j -
Fitoterapia Jul 2023Oxymatrine (OMT), was identified as a quinolizidine alkaloid, which was one of the major matrine-type alkaloids extracted from Sophora medicinal plants. Growing studies... (Review)
Review
Oxymatrine (OMT), was identified as a quinolizidine alkaloid, which was one of the major matrine-type alkaloids extracted from Sophora medicinal plants. Growing studies revealed that OMT has a wide range of beneficial pharmacological values, consisting of anticancer, antidiabetic, antivirus, and antiinflammtion, as well as the protective activities to the brain, liver, heart, lung, vascular, gastrointestinal, bone, kidney, and skin organs. Various in vitro and in vivo models of pharmacological actions were recorded in regard to the usage of alkaloidal OMT. Mechanisms underlying anticancer activity of this compound may have been possibly involved anti-proliferation, invasion, migration, angiogenesis, epithelial-mesenchymal transition of cells, autophagy, especially apoptotic cell deaths. OMT could reduce hyperglycemia and hyperlipemia in a high-fat diet and streptozotocin-stimulated diabetic mice by improving insulin secretion and sensitivity. OMT suppressed gastric ulcer via gastric inflammatory and oxidative inhibitions, and pro-apoptotic actions. It turns out that OMT is relatively safe for cell and animal experiments. In this study, we offer a systematic review of natural occurrence, pharmacological potentials, possible mechanisms of action, pharmacokinetics, and bioavailability. Clinical research with OMT is needed to extensively elucidate its health potential benefits.
Topics: Mice; Animals; Diabetes Mellitus, Experimental; Molecular Structure; Alkaloids; Matrines; Quinolizines
PubMed: 37295753
DOI: 10.1016/j.fitote.2023.105565 -
Natural Product Reports Aug 2020Covering: 2000 to 2019Rapid access to genomic data has facilitated the identification of the biosynthetic enzyme genes of alkaloid natural products and elucidation of... (Review)
Review
Covering: 2000 to 2019Rapid access to genomic data has facilitated the identification of the biosynthetic enzyme genes of alkaloid natural products and elucidation of their biosynthetic pathways. Enzymes for the rapid construction of molecular scaffolds and versatile modifications during the late-stage biosynthesis of complex molecular skeletons constitute unique features of biosynthetic machineries. For example, enzymes involved in an alkaloid biosynthesis. In this review, we discuss three types of useful enzymes and enzymatic reactions that have been found in the biosynthetic studies of several alkaloids, and discuss their applications for the total synthesis of natural alkaloids and their derivatives. The selected examples include a single non-ribosomal peptide synthetase SfmC that catalyzes key Pictet-Spengler reactions, which construct a characteristic tetrahydroisoquinoline skeleton in antitumor antibiotics such as saframycin, prenylation-oxidative modification enzymes involved in the biosynthesis of fungal tremorgenic mycotoxins such as penitrem as well as versatile Diels-Alderases recently discovered in the biosynthesis of plant monoterpene indole alkaloids of iboga and aspidosperma type.
Topics: Alkaloids; Anti-Bacterial Agents; Biological Products; Biosynthetic Pathways; Catalysis; Peptide Synthases
PubMed: 32141467
DOI: 10.1039/c9np00073a