Evaluation of Pyridoacridine Alkaloids in a Zebrafish Phenotypic Assay

Three new minor components, the pyridoacridine alkaloids 1-hydroxy-deoxyamphimedine (1), 3-hydroxy-deoxyamphimedine (2), debromopetrosamine (3), and three known compounds, amphimedine (4), neoamphimedine (5) and deoxyamphimedine (6), have been isolated from the sponge Xestospongia cf. carbonaria, collected in Palau. Structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Compounds 1–6 were evaluated in a zebrafish phenotype-based assay. Amphimedine (4) was the only compound that caused a phenotype in zebrafish embryos at 30 μM. No phenotype other than death was observed for compounds 1–3, 5, 6.     

Deoxyamphimedine,a Pyridoacridine Alkaloid,Damages DNA via the Production of Reactive Oxygen Species

Marine pyridoacridines are a class of aromatic chemicals that share an 11H-pyrido[4,3,2-mn]acridine skeleton. Pyridoacridine alkaloids display diverse biological activities including cytotoxicity, fungicidal and bactericidal properties, production of reactive oxygen species (ROS) and topoisomerase inhibition. These activities are often dependent on slight modifications to the pyridoacridine skeleton. Here we demonstrate that while structurally similar to neoamphimedine and amphimedine, the biological activity of deoxyamphimedine differs greatly. Deoxyamphimedine damages DNA in vitro independent of topoisomerase enzymes through the generation of reactive oxygen species. Its activity was decreased in low oxygen, with the removal of a reducing agent and in the presence of anti-oxidants. Deoxyamphimedine also showed enhanced toxicity in cells sensitive to single or double strand DNA breaks, consistent with the in vitro activity.     

Anticancer activity evaluation of kuanoniamines A and C isolated from the marine sponge Oceanapia sagittaria, collected from the Gulf of Thailand

The pyridoacridine alkaloids kuanoniamines A and C were isolated together with 24 α-methylcholestanol, p-hydroxybenzaldehyde, p-hydroxybenzoic acid, phenylacetic acid and 3-formylindole from the ethyl acetate extract of the marine sponge Oceanapia sagittaria (Sollas), collected from the Gulf of Thailand. Kuanoniamines A and C were evaluated for their effect on the growth of five human tumour and a non-tumour cell lines, as well as on the proliferation of human lymphocytes. Kuanoniamine A was found to be a potent growth inhibitor of all the tumour and a non-tumour cell lines while kuanoniamine C was less potent but showed high selectivity toward the estrogen dependent (ER+) breast cancer cell line. Kuanoniamine A has shown to be a more potent inhibitor of DNA synthesis than kuanoniamine C. Kuanoniamine A was also found to cause an extensive reduction of the MCF-7 cells in G2/M phase as well as an increase in the apoptotic cells.     

Marine-Derived Indole Alkaloids and Their Biological and Pharmacological Activities

Novel secondary metabolites from marine macroorganisms and marine-derived microorganisms have been intensively investigated in the last few decades. Several classes of compounds, especially indole alkaloids, have been a target for evaluating biological and pharmacological activities. As one of the most promising classes of compounds, indole alkaloids possess not only intriguing structural features but also a wide range of biological/pharmacological activities including antimicrobial, anti-inflammatory, anticancer, antidiabetic, and antiparasitic activities. This review reports the indole alkaloids isolated during the period of 2016–2021 and their relevant biological/pharmacological activities. The marine-derived indole alkaloids reported from 2016 to 2021 were collected from various scientific databases. A total of 186 indole alkaloids from various marine organisms including fungi, bacteria, sponges, bryozoans, mangroves, and algae, are described. Despite the described bioactivities, further evaluation including their mechanisms of action and biological targets is needed to determine which of these indole alkaloids are worth studying to obtain lead compounds for the development of new drugs.     

Genus Nocardiopsis: A Prolific Producer of Natural Products

Actinomycetes are currently one of the major sources of bioactive secondary metabolites used for medicine development. Accumulating evidence has shown that Nocardiopsis, a key class of actinomycetes, has the ability to produce novel bioactive natural products. This review covers the sources, distribution, bioactivities, biosynthesis, and structural characteristics of compounds isolated from Nocardiopsis in the period between March 2018 and 2021. Our results reveal that 67% of Nocardiopsis-derived natural products are reported for the first time, and 73% of them are isolated from marine Nocardiopsis. The chemical structures of the Nocardiopsis-derived compounds have diverse skeletons, concentrating on the categories of polyketides, peptides, terphenyls, and alkaloids. Almost 50% of the natural products isolated from Nocardiopsis have been discovered to display various bioactivities. These results fully demonstrate the great potential of the genus Nocardiopsis to produce novel bioactive secondary metabolites that may serve as a structural foundation for the development of novel drugs.     

Marine Alkaloids: Compounds with In Vivo Activity and Chemical Synthesis

Marine alkaloids comprise a class of compounds with several nitrogenated structures that can be explored as potential natural bioactive compounds. The scientific interest in these compounds has been increasing in the last decades, and many studies have been published elucidating their chemical structure and biological effects in vitro. Following this trend, the number of in vivo studies reporting the health-related properties of marine alkaloids has been increasing and providing more information about the effects in complex organisms. Experiments with animals, especially mice and zebrafish, are revealing the potential health benefits against cancer development, cardiovascular diseases, seizures, Alzheimer’s disease, mental health disorders, inflammatory diseases, osteoporosis, cystic fibrosis, oxidative stress, human parasites, and microbial infections in vivo. Although major efforts are still necessary to increase the knowledge, especially about the translation value of the information obtained from in vivo experiments to clinical trials, marine alkaloids are promising candidates for further experiments in drug development.     

Large-scale biotechnological production of the antileukemic marine natural product sorbicillactone A

In the search for novel bioactive compounds from sponge-derived microorganisms, we have recently identified two structurally and biosynthetically unprecedented fungal metabolites, the novel-type alkaloids sorbicillactone A and sorbicillactone B. Sorbicillactone A is active against leukemia cells without showing notable cytotoxicity. Therefore, we have developed an efficient process for its biotechnological production and isolation on a large scale supplying sufficient material for the ongoing preclinical investigations and structure-activity relationship (SAR) studies.     

Novel Alkaloids from Marine Actinobacteria: Discovery and Characterization

The marine environment is an excellent resource for natural products with therapeutic potential. Its microbial inhabitants, often associated with other marine organisms, are specialized in the synthesis of bioactive secondary metabolites. Similar to their terrestrial counterparts, marine Actinobacteria are a prevalent source of these natural products. Here, we discuss 77 newly discovered alkaloids produced by such marine Actinobacteria between 2017 and mid-2021, as well as the strategies employed in their elucidation. While 12 different classes of alkaloids were unraveled, indoles, diketopiperazines, glutarimides, indolizidines, and pyrroles were most dominant. Discoveries were mainly based on experimental approaches where microbial extracts were analyzed in relation to novel compounds. Although such experimental procedures have proven useful in the past, the methodologies need adaptations to limit the chance of compound rediscovery. On the other hand, genome mining provides a different angle for natural product discovery. While the technology is still relatively young compared to experimental screening, significant improvement has been made in recent years. Together with synthetic biology tools, both genome mining and extract screening provide excellent opportunities for continued drug discovery from marine Actinobacteria.     

New One-Pot Methodologies for the Modification or Synthesis of Alkaloid Scaffolds

There are several avenues by which promising bioactive natural products can be produced in sufficient quantities to enable lead optimization and medicinal chemistry studies. The total synthesis of natural products is an important, but sometimes difficult, approach and requires the development of innovative synthetic methodologies to simplify the synthesis of complex molecules. Various classes of natural product alkaloids are both common and widely distributed in plants, bacteria, fungi, insects and marine organisms. This mini-review will discuss the scope, mechanistic insights and enantioselectivity aspects of selected examples of recently developed one-pot methods that have been published in 2009 for the synthesis of substituted piperidines, quinolizidines, pyrrolidines, hexahydropyrrolizines, octahydroindolizines and γ-lactams. In addition, progress on the synthesis of β-carboline (manzamine) alkaloids will also be discussed.     

Marine Indole Alkaloids—Isolation,Structure and Bioactivities

Indole alkaloids are heterocyclic natural products with extensive pharmacological activities. As an important source of lead compounds, many clinical drugs have been derived from natural indole compounds. Marine indole alkaloids, from unique marine environments with high pressure, high salt and low temperature, exhibit structural diversity with various bioactivities, which attracts the attention of drug researchers. This article is a continuation of the previous two comprehensive reviews and covers the literature on marine indole alkaloids published from 2015 to 2021, with 472 new or structure-revised compounds categorized by sources into marine microorganisms, invertebrates, and plant-derived. The structures and bioactivities demonstrated in this article will benefit the synthesis and pharmacological activity study for marine indole alkaloids on their way to clinical drugs.     

An Improved High Yield Total Synthesis and Cytotoxicity Study of the Marine Alkaloid Neoamphimedine: An ATP-Competitive Inhibitor of Topoisomerase IIα and Potent Anticancer Agent

Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (≤6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC₅₀ values) in all, with significant potency against colorectal cancer (lowest IC₅₀ = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis.     

Bioactive Alkaloids from the Sea: A Review

In our ongoing search for bioactive substances from marine organisms, novel alkaloids have been isolated. Pinnatoxins and pinnamine, potent shellfish poisons, were purified from the Okinawan bivalve Pinna muricata. Pinnatoxins activate Ca²⁺ channels. Halichlorine was isolated from the marine sponge Halichondria okadai. This compound inhibits the induction of VCAM-1. Drugs that block VCAM-1 may be useful for treating coronary artery diseases, angina, and noncardiovascular inflammatory diseases. Pinnaic acids, which are cPLA₂ inhibitors, were also obtained from P. muricata. Interestingly, the structures of pinnaic acids are closely related to that of halichlorine. Norzoanthamine hydrochloride, isolated from the colonial zoanthid Zoanthus sp., suppresses decreases in bone weight and strength in ovariectomized mice, and could be a good candidate for an osteoporotic drug. Ircinamine, purified from the marine sponge Ircinia sp., has a reactive thioester. Aburatubolactams, inhibitors of superoxide anion generation, were isolated from Streptomyces sp. This article covers the bioactive marine alkaloids that have been recently isolated by this research group.     

Anticancer Activities of Plant Secondary Metabolites: Rice Callus Suspension Culture as a New Paradigm

Plant natural products including alkaloids,polyphenols,terpenoids and flavonoids have been reported to exert anticancer activity by targeting various metabolic pathways.The biological pathways regulated by plant products can serve as novel drug targets.Plant natural compounds or their derivatives used for cancer treatment and some novel plant-based compounds which are used in clinical trials were discussed.Callus suspension culture with secondary metabolites can provide a continuous source of plant pharmaceuticals without time and space limitations.Previous research has shown that rice callus suspension culture can kill>95%cancer cells with no significant effect on the growth of normal cells.The role of candidate genes and metabolites which are likely to be involved in the process and their potential to serve as anticancer and anti-inflammatory agents were discussed.Large scale production of plant callus suspension culture and its constituents can be achieved using elicitors which enhance specific secondary metabolites combined with bioprocess technology.     

Recent Advances in the Synthesis of Marine-Derived Alkaloids via Enzymatic Reactions

Alkaloids are a large and structurally diverse group of marine-derived natural products. Most marine-derived alkaloids are biologically active and show promising applications in modern (agro)chemical, pharmaceutical, and fine chemical industries. Different approaches have been established to access these marine-derived alkaloids. Among these employed methods, biotechnological approaches, namely, (chemo)enzymatic synthesis, have significant potential for playing a central role in alkaloid production on an industrial scale. In this review, we discuss research progress on marine-derived alkaloid synthesis via enzymatic reactions and note the advantages and disadvantages of their applications for industrial production, as well as green chemistry for marine natural product research.     

Bioactive compound synthetic capacity and ecological significance of marine bacterial genus pseudoalteromonas

The genus Pseudoalteromonas is a marine group of bacteria belonging to the class Gammaproteobacteria that has come to attention in the natural product and microbial ecology science fields in the last decade. Pigmented species of the genus have been shown to produce an array of low and high molecular weight compounds with antimicrobial, anti-fouling, algicidal and various pharmaceutically-relevant activities. Compounds formed include toxic proteins, polyanionic exopolymers, substituted phenolic and pyrolle-containing alkaloids, cyclic peptides and a range of bromine-substituted compounds. Ecologically, Pseudoalteromonas appears significant and to date has been shown to influence biofilm formation in various marine econiches; involved in predator-like interactions within the microbial loop; influence settlement, germination and metamorphosis of various invertebrate and algal species; and may also be adopted by marine flora and fauna as defensive agents. Studies have been so far limited to a relatively small subset of strains compared to the known diversity of the genus suggesting that many more discoveries of novel natural products as well as ecological connections these may have in the marine ecosystem remain to be made.     

Zorrimidazolone, a bioactive alkaloid from the non-indigenous mediterranean stolidobranch Polyandrocarpa zorritensis

Chemical analysis of the Mediterranean ascidian Polyandrocarpa zorritensis (Van Name 1931) resulted in the isolation of a series of molecules including two monoindole alkaloids, 3-indolylglyoxylic acid (3) and its methyl ester (4), 4-hydroxy-3-methoxyphenylglyoxylic acid methyl ester (1) and a new alkaloid we named zorrimidazolone (2). The structure of the novel compound 2 has been elucidated by spectroscopic analysis and bioactivity of all compounds has been investigated. Zorrimidazolone (2) showed a modest cytotoxic activity against C6 rat glioma cell line.     

Untapped Potential of Marine-Associated Cladosporium Species: An Overview on Secondary Metabolites,Biotechnological Relevance,and Biological Activities

The marine environment is an underexplored treasure that hosts huge biodiversity of microorganisms. Marine-derived fungi are a rich source of novel metabolites with unique structural features, bioactivities, and biotechnological applications. Marine-associated Cladosporium species have attracted considerable interest because of their ability to produce a wide array of metabolites, including alkaloids, macrolides, diketopiperazines, pyrones, tetralones, sterols, phenolics, terpenes, lactones, and tetramic acid derivatives that possess versatile bioactivities. Moreover, they produce diverse enzymes with biotechnological and industrial relevance. This review gives an overview on the Cladosporium species derived from marine habitats, including their metabolites and bioactivities, as well as the industrial and biotechnological potential of these species. In the current review, 286 compounds have been listed based on the reported data from 1998 until July 2021. Moreover, more than 175 references have been cited.     

Isolation and Total Synthesis of Stolonines A–C,Unique Taurine Amides from the Australian Marine Tunicate Cnemidocarpa stolonifera

Cnemidocarpa stolonifera is an underexplored marine tunicate that only occurs on the tropical to subtropical East Coast of Australia, with only two pyridoacridine compounds reported previously. Qualitative analysis of the lead-like enhanced fractions of C. stolonifera by LC-MS dual electrospray ionization coupled with PDA and ELSD detectors led to the identification of three new natural products, stolonines A–C (1–3), belonging to the taurine amide structure class. Structures of the new compounds were determined by NMR and MS analyses and later verified by total synthesis. This is the first time that the conjugates of taurine with 3-indoleglyoxylic acid, quinoline-2-carboxylic acid and β-carboline-3-carboxylic acid present in stolonines A–C (1–3), respectively, have been reported. An immunofluorescence assay on PC3 cells indicated that compounds 1 and 3 increased cell size, induced mitochondrial texture elongation, and caused apoptosis in PC3 cells.     

Liquid Chromatography-Mass Spectrometry-Based Rapid Secondary-Metabolite Profiling of Marine Pseudoalteromonas sp. M2

The ocean is a rich resource of flora, fauna, and food. A wild-type bacterial strain showing confluent growth on marine agar with antibacterial activity was isolated from marine water, identified using 16S rDNA sequence analysis as Pseudoalteromonas sp., and designated as strain M2. This strain was found to produce various secondary metabolites including quinolone alkaloids. Using high-resolution mass spectrometry (MS) and nuclear magnetic resonance (NMR) analysis, we identified nine secondary metabolites of 4-hydroxy-2-alkylquinoline (pseudane-III, IV, V, VI, VII, VIII, IX, X, and XI). Additionally, this strain produced two novel, closely related compounds, 2-isopentylqunoline-4-one and 2-(2,3-dimetylbutyl)qunoline-4-(1H)-one, which have not been previously reported from marine bacteria. From the metabolites produced by Pseudoalteromonas sp. M2, 2-(2,3-dimethylbutyl)quinolin-4-one, pseudane-VI, and pseudane-VII inhibited melanin synthesis in Melan-A cells by 23.0%, 28.2%, and 42.7%, respectively, wherein pseudane-VII showed the highest inhibition at 8 µg/mL. The results of this study suggest that liquid chromatography (LC)-MS/MS-based metabolite screening effectively improves the efficiency of novel metabolite discovery. Additionally, these compounds are promising candidates for further bioactivity development.     

Subereamolline A as a Potent Breast Cancer Migration, Invasion and Proliferation Inhibitor and Bioactive Dibrominated Alkaloids from the Red Sea Sponge Pseudoceratina arabica

A new collection of several Red Sea sponges was investigated for the discovery of potential breast cancer migration inhibitors. Extracts of the Verongid sponges Pseudoceratina arabica and Suberea mollis were selected. Bioassay-directed fractionation of both sponges, using the wound-healing assay, resulted into the isolation of several new and known brominated alkaloids. Active fractions of the sponge Pseudoceratina arabica afforded five new alkaloids, ceratinines A–E (2–6), together with the known alkaloids moloka’iamine (1), hydroxymoloka’iamine (7) and moloka’iakitamide (8). The active fraction of the sponge Suberea mollis afforded the three known alkaloids subereamolline A (9), aerothionin (10) and homoaerothionin (11). Ceratinine B (3) possesses an unprecedented 5,7-dibrominated dihydroindole moiety with an epoxy ring on the side chain of a fully substituted aromatic moiety. Ceratinines D (5) and E (6) possess a terminal formamide moiety at the ethylamine side chain. Subereamolline A (9) potently inhibited the migration and invasion of the highly metastatic human breast cancer cells MDA-MB-231 at the nanomolar doses. Subereamolline A and related brominated alkaloids are novel scaffolds appropriate for further future use for the control of metastatic breast cancer.