ABSTRACT
Marine polycyclic ether natural products have gained significant interest from the chemical community due to their impressively huge molecular architecture and diverse biological functions. The structure assignment of this class of extraordinarily complex natural products has mainly relied on NMR spectroscopic analysis. However, NMR spectroscopic analysis has its own limitations, including configurational assignment of stereogenic centers within conformationally flexible systems. Chemical shift deviation analysis of synthetic model compounds is a reliable means to assign the relative configuration of "difficult" stereogenic centers. The complete configurational assignment must be ultimately established through total synthesis. The aim of this review is to summarize the indispensable role of organic synthesis in stereochemical assignment of marine polycyclic ethers.
Subject(s)
Aquatic Organisms/metabolism , Ethers, Cyclic/chemical synthesis , Chemistry Techniques, Synthetic , Ciguatoxins/chemical synthesis , Ciguatoxins/isolation & purification , Ethers/chemical synthesis , Ethers/isolation & purification , Ethers, Cyclic/isolation & purification , Humans , Magnetic Resonance Spectroscopy , Marine Toxins/chemical synthesis , Marine Toxins/isolation & purification , Molecular Structure , Oxocins/chemical synthesis , Oxocins/isolation & purification , Polymers/chemical synthesis , Polymers/isolation & purification , Secondary Metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Cancer metastasis is a complex process involving highly motile tumor cells that breach tissue barriers, enter the bloodstream and lymphatic system, and disseminate throughout the body as circulating tumor cells. The primary cellular mechanism contributing to these critical events is the reorganization of the actin cytoskeleton. Mycalolide B (MycB) is an actin-targeting marine macrolide that can suppress proliferation, migration, and invasion of breast and ovarian cancer cells at low nanomolar doses. Through structure-activity relationship studies focused on the actin-binding tail region (C24-C35) of MycB, we identified a potent truncated derivative that inhibits polymerization of G-actin and severs F-actin by binding to actin's barbed end cleft. Biological analyses of this miniature MycB derivative demonstrate that it causes a rapid collapse of the actin cytoskeleton in ovarian cancer cells and impairs cancer cell motility and invasion of the extracellular matrix (ECM) by inhibiting invadopodia-mediated ECM degradation. These studies provide essential proof-of-principle for developing actin-targeting therapeutic agents to block cancer metastasis and establish a synthetically tractable barbed end-binding pharmacophore that can be further improved by adding targeting groups for precision drug design.
Subject(s)
Actins/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Extracellular Matrix/drug effects , Marine Toxins/pharmacology , Oxazoles/pharmacology , Actins/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Movement/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Extracellular Matrix/metabolism , Female , Humans , Marine Toxins/chemical synthesis , Marine Toxins/chemistry , Models, Molecular , Molecular Structure , Oxazoles/chemical synthesis , Oxazoles/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Synthesis of the fused polycyclic ether motif comprising the EFG rings of the marine ladder polyethers tamulamides A and B has been achieved via two different etherification strategies. Ultimately, a reductive etherification approach proved most successful due to tolerance of the G ring substitution and provided the EFG 6,7,6 ring system in 58% yield.
Subject(s)
Marine Toxins/chemical synthesis , Oxocins/chemical synthesis , Marine Toxins/chemistry , Molecular Conformation , Oxocins/chemistry , StereoisomerismABSTRACT
Azaspiracid-34 (AZA34) is a recently described structurally unique member of the azaspiracid class of marine neurotoxins. Its novel structure, tentatively assigned on the basis of MS and 1H NMR spectroscopy, is accompanied by a 5.5-fold higher level of toxicity against Jurkat T lymphocytes than AZA1. To completely assign the structure of AZA34 and provide material for in-depth biological evaluation and detection, synthetic access to AZA34 was targeted. This began with the convergent and stereoselective assembly of the C1-C19 domain of AZA34 designed to dovetail with the recent total synthesis approach to AZA3.
Subject(s)
Jurkat Cells/cytology , Marine Toxins/toxicity , Neurotoxins/toxicity , Spiro Compounds/chemical synthesis , Humans , Jurkat Cells/chemistry , Magnetic Resonance Spectroscopy , Marine Toxins/chemical synthesis , Marine Toxins/chemistry , Molecular Structure , Spiro Compounds/chemistryABSTRACT
Marine natural products and biologically active compounds often contain cyclic ether units. Thus, regio- and stereoselective construction of these structures has long been a topic of interest in organic synthesis. This review summarizes new synthetic approaches to polycyclic ether natural products utilizing the features of chemical elements.
Subject(s)
Biological Products/chemical synthesis , Elements , Ethers, Cyclic/chemical synthesis , Marine Biology , Marine Toxins/chemical synthesis , Oxocins/chemical synthesis , Animals , Biological Products/chemistry , Catalysis , Chemistry, Organic/methods , Ethers, Cyclic/chemistry , Gold , Hydrophobic and Hydrophilic Interactions , Marine Toxins/chemistry , Mice , Molecular Conformation , Organic Chemistry Phenomena , Oxocins/chemistry , Rhenium/chemistry , StereoisomerismABSTRACT
An aplyronine A-swinholide A hybrid, consisting of the macrolactone part of aplyronine A and the side chain part of swinholide A, was designed, synthesized, and evaluated for biological activities. The hybrid retained strong cytotoxicity and actin-depolymerizing activity. In addition, the hybrid induced protein-protein interactions (PPI) between actin and tubulin in the manner of aplyronine A.
Subject(s)
Actins/metabolism , Antineoplastic Agents/pharmacology , Macrolides/pharmacology , Marine Toxins/pharmacology , Tubulin/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , HeLa Cells , Humans , Macrolides/chemical synthesis , Macrolides/chemistry , Marine Toxins/chemical synthesis , Marine Toxins/chemistry , Molecular Conformation , Protein Binding , Stereoisomerism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
Synthesis of the fused tetrahydrofuran motif comprising the ABC rings of the marine ladder polyethers tamulamides A and B has been achieved via two different polyepoxide cascade strategies. Investigations into a triepoxide cascade under aqueous conditions revealed the importance of the electronic nature of the cascade end-group with this initial approach. Ultimately, a diepoxide cascade under basic conditions proved most successful, providing the ABC tetrahydropyran triad in 41% yield.
Subject(s)
Marine Toxins/chemical synthesis , Oxocins/chemical synthesis , Cyclization , Epoxy Compounds/chemistry , Furans/chemistryABSTRACT
Diverse hydrogen-mediated C-C couplings enable construction of the actin-binding marine polyketide swinholide A in only 15 steps (longest linear sequence), roughly half the steps required in two prior total syntheses. The redox-economy, chemo- and stereoselectivity embodied by this new class of C-C couplings are shown to evoke a step-change in efficiency.
Subject(s)
Carbon/chemistry , Hydrogen/chemistry , Marine Toxins/chemistry , Marine Toxins/chemical synthesis , Chemistry Techniques, SyntheticABSTRACT
The paralytic shellfish poisons are a collection of guanidine-containing natural products that are biosynthesized by prokaryote and eukaryote marine organisms. These compounds bind and inhibit isoforms of the mammalian voltage-gated Na(+) ion channel at concentrations ranging from 10(-11) to 10(-5) M. Here, we describe the de novo synthesis of three paralytic shellfish poisons, gonyautoxin 2, gonyautoxin 3, and 11,11-dihydroxysaxitoxin. Key steps include a diastereoselective Pictet-Spengler reaction and an intramolecular amination of an N-guanidyl pyrrole by a sulfonyl guanidine. The IC50's of GTX 2, GTX 3, and 11,11-dhSTX have been measured against rat NaV1.4, and are found to be 22 nM, 15 nM, and 2.2 µM, respectively.
Subject(s)
Marine Toxins/chemical synthesis , Saxitoxin/analogs & derivatives , Saxitoxin/chemical synthesis , Amines/chemistry , Animals , Cyclization , Marine Toxins/pharmacology , Muscle Proteins/antagonists & inhibitors , Pyrroles/chemistry , Rats , Saxitoxin/pharmacology , Shellfish , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/pharmacology , Sodium Channels , StereoisomerismABSTRACT
An efficient synthesis of the C22-C40 domain of the azaspiracids is described. The synthetic route features a Nozaki-Hiyama-Kishi (NHK) coupling and chelation controlled Mukaiyama aldol reaction to access an acyclic intermediate and a double-intramolecular-hetero-Michael addition (DIHMA) to provide the FG-ring system bridged ketal.
Subject(s)
Marine Toxins/chemical synthesis , Spiro Compounds/chemical synthesis , Marine Toxins/chemistry , Molecular Structure , Spiro Compounds/chemistry , StereoisomerismABSTRACT
Using stereo- and site-selective C-H allylation and crotylation of unprotected diols, an intermediate in the synthesis of premisakinolide A (bistheonellic acid B) that was previously made in 16-27 (LLS) steps is now prepared in only nine steps. This fragment also represents a synthesis of C(19)-C(32) of the actin-binding macrodiolide swinholide A.
Subject(s)
Macrolides/chemical synthesis , Marine Toxins/chemical synthesis , Actins/metabolism , Alcohols/chemistry , Catalysis , Macrolides/chemistry , Marine Toxins/chemistry , Molecular Structure , StereoisomerismABSTRACT
We recently reported the chemical synthesis and identification of the genetically predicted biosynthetic intermediates of saxitoxin (STX), including a 2-aminoimidazole-bearing monoguanidine compound (Int-C'2) in two paralytic shellfish toxin (PST)-producing microorganisms. In this study, we achieved the direct conversion of Int-C'2 into a tricyclic bisguanidine compound (called Cyclic-C'), which is structurally related to STX, through oxidative intramolecular guanidine transfer to 2-aminoimidazole catalyzed by Pd/C under basic conditions in air. By using HPLC-MS analysis, Cyclic-C' was also identified in the PST-producing microorganisms, suggesting that Cyclic-C' is either another biosynthetic intermediate or a shunt product of PSTs. In addition, a weak inhibitory activity of Cyclic-C' to the voltage-gated sodium channels was detected by using a cell-based assay.
Subject(s)
Guanidine/analogs & derivatives , Marine Toxins/chemistry , Saxitoxin/chemistry , Animals , Catalysis , Cell Line , Cyclization , Dinoflagellida/chemistry , Guanidine/chemical synthesis , Guanidine/pharmacology , Imidazoles/chemistry , Marine Toxins/chemical synthesis , Marine Toxins/pharmacology , Mice , Oxidation-Reduction , Shellfish/analysis , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolismABSTRACT
From a small group of exotic compounds isolated only two decades ago, Cyclic Imine (CI) toxins have become a major class of marine toxins with global distribution. Their distinct chemical structure, biological mechanism of action, and intricate chemistry ensures that CI toxins will continue to be the subject of fascinating fundamental studies in the broad fields of chemistry, chemical biology, and toxicology. The worldwide occurrence of potent CI toxins in marine environments, their accumulation in shellfish, and chemical stability are important considerations in assessing risk factors for human health. This review article aims to provide an account of chemistry, biology, and toxicology of CI toxins from their discovery to the present day.
Subject(s)
Biological Products/chemical synthesis , Biological Products/pharmacology , Imines/chemistry , Marine Toxins/chemical synthesis , Marine Toxins/pharmacology , Biological Products/chemistry , Environment , Humans , Imines/chemical synthesis , Imines/pharmacology , Marine Toxins/chemistry , Molecular Structure , ShellfishABSTRACT
A theoretical study to elucidate the mechanistic aspects involved in the tosylation-cyclization reaction of diastereomeric phytosphingosines 1a-1d to jaspines 4a-4d is presented. The stereochemistry of the starting stereoisomers is crucial for the development of weak interactions, both in the reactants and in the transition states. The analysis of the energy barriers of each elementary reaction is consistent with the observed reluctance of tosylate 2d to undergo cyclization. In addition, the initial tosylation can be identified as the limiting step in cyclizations from la and 1b.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Marine Toxins/chemical synthesis , Sphingosine/analogs & derivatives , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Cyclization , Marine Toxins/chemistry , Models, Molecular , Molecular Structure , Sphingosine/chemistryABSTRACT
Cylindrospermopsin (CYN) is a cyanobacterial toxin associated with human and animal poisonings. Due to its toxicity in combination with its widespread occurrence, the development of reliable methods for selective, sensitive detection and accurate quantification is mandatory. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis using stable isotope dilution analysis (SIDA) represents an ideal tool for this purpose. U-[(15)N5]-CYN was synthesized by culturing Aphanizomenon flos-aquae in Na(15)NO3-containing cyanobacteria growth medium followed by a cleanup using graphitized carbon black columns and mass spectrometric characterization. Subsequently, a SIDA-LC-MS/MS method for the quantification of CYN in freshwater and Brassica matrices was developed showing satisfactory performance data. The recovery ranged between 98 and 103 %; the limit of quantification was 15 ng/L in freshwater and 50 µg/kg dry weight in Brassica samples. The novel SIDA was applied for CYN determination in real freshwater samples as well as in kale and in vegetable mustard exposed to toxin-containing irrigation water. Two of the freshwater samples taken from German lakes were found to be CYN-contaminated above limit of quantification (17.9 and 60.8 ng/L). CYN is systemically available to the examined vegetable species after exposure of the rootstock leading to CYN mass fractions in kale and vegetable mustard leaves of 15.0 µg/kg fresh weight and 23.9 µg/kg fresh weight, respectively. CYN measurements in both matrices are exemplary for the versatile applicability of the developed method in environmental analysis.
Subject(s)
Bacterial Toxins/chemistry , Brassica/chemistry , Fresh Water/analysis , Indicator Dilution Techniques , Marine Toxins/chemistry , Microcystins/chemistry , Tandem Mass Spectrometry/methods , Uracil/analogs & derivatives , Alkaloids , Bacterial Toxins/chemical synthesis , Bacterial Toxins/metabolism , Brassica/microbiology , Cyanobacteria/metabolism , Cyanobacteria Toxins , Fresh Water/microbiology , Indicator Dilution Techniques/standards , Isotope Labeling , Marine Toxins/chemical synthesis , Marine Toxins/metabolism , Microcystins/chemical synthesis , Microcystins/metabolism , Nitrogen Isotopes/chemistry , Reference Standards , Tandem Mass Spectrometry/instrumentation , Tandem Mass Spectrometry/standards , Uracil/chemical synthesis , Uracil/chemistry , Uracil/metabolismABSTRACT
Stereoselective synthesis of the C'D'E'F' ring system of maitotoxin was achieved starting from the E' ring through successive formation of the D' and C' rings based on SmI2-mediated reductive cyclization. Construction of the F' ring was accomplished via Suzuki-Miyaura cross-coupling with a side chain fragment and Pd(II)-catalyzed cyclization of an allylic alcohol. The C'D'E'F' ring system inhibited maitotoxin-induced Ca(2+) influx in rat glioma C6 cells with an IC50 value of 59 µM.
Subject(s)
Marine Toxins/antagonists & inhibitors , Marine Toxins/chemistry , Marine Toxins/chemical synthesis , Oxocins/antagonists & inhibitors , Oxocins/chemistry , Oxocins/chemical synthesis , Palladium/chemistry , Polycyclic Compounds/chemical synthesis , Propanols/chemistry , Animals , Catalysis , Cyclization , Inhibitory Concentration 50 , Molecular Structure , Polycyclic Compounds/chemistry , Rats , StereoisomerismABSTRACT
Conversion of a simple furan into the ABCD-ring skeleton of the azaspiracids via a singlet oxygen-initiated one-pot process has been accomplished.
Subject(s)
Furans/chemistry , Furans/chemical synthesis , Marine Toxins/chemistry , Marine Toxins/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Molecular Structure , Singlet OxygenABSTRACT
An efficient synthesis of the C1-C21 fragment of azaspiracids-1 and -3 is described. This features a Nozaki-Hiyama-Kishi reaction to couple the AB and CD ring precursors and formation of the THF-fused ABCD trioxadispiroketal system under thermodynamic conditions.
Subject(s)
Furans/chemical synthesis , Marine Toxins/chemical synthesis , Pyrans/chemical synthesis , Spiro Compounds/chemical synthesis , Furans/chemistry , Marine Toxins/chemistry , Molecular Structure , Pyrans/chemistry , Spiro Compounds/chemistry , Stereoisomerism , ThermodynamicsABSTRACT
A non-classical route to the key CDE-ring fragment of the pectenotoxins has been developed which showcases a remarkable singlet oxygen-mediated cascade reaction sequence to install the complete DE ring system.
Subject(s)
Macrolides/chemistry , Macrolides/chemical synthesis , Marine Toxins/chemistry , Marine Toxins/chemical synthesis , Singlet Oxygen/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Chemistry Techniques, SyntheticABSTRACT
Dinoflagellate microalgae are an important source of marine biotoxins. Bioactives from dinoflagellates are attracting increasing attention because of their impact on the safety of seafood and potential uses in biomedical, toxicological and pharmacological research. Here we review the potential applications of dinoflagellate toxins and the methods for producing them. Only sparing quantities of dinoflagellate toxins are generally available and this hinders bioactivity characterization and evaluation in possible applications. Approaches to production of increased quantities of dinoflagellate bioactives are discussed. Although many dinoflagellates are fragile and grow slowly, controlled culture in bioreactors appears to be generally suitable for producing many of the metabolites of interest.