Tricyclic Guanidine Research Articles

Fused Tricyclic Guanidine Alkaloids: Insights into Their Structure, Synthesis and Bioactivity.

A marine natural product possesses a diverse and unique scaffold that contributes to a vast array of bioactivities. Tricyclic guanidine alkaloids are a type of scaffold found only in marine natural products. These rare skeletons exhibit a wide range of biological applications, but their synthetic approaches are still limited. Various stereochemical assignments of the compounds remain unresolved. Batzelladine and ptilocaulins are an area of high interest in research on tricyclic guanidine alkaloids. In addition, mirabilins and netamines are among the other tricyclic guanidine alkaloids that contain the ptilocaulin skeleton. Due to the different structural configurations of batzelladine and ptilocaulin, these two main skeletons are afforded attention in many reports. These two main skeletons exhibit different kinds of compounds by varying their ester chain and sidechain. The synthetic approaches to tricyclic guanidine alkaloids, especially the batzelladine and ptilocaulin skeletons, are discussed. Moreover, this review compiles the first and latest research on the synthesis of these compounds and their bioactivities, dating from the 1980s to 2022.

Treatment of cylindrospermopsin by hydroxyl and sulfate radicals: Does degradation equal detoxification?

Drinking water treatment ultimately aims to provide safe and harmless drinking water. Therefore, the suitability of a treatment process should not only be assessed based on reducing the concentration os a pollutant concentration but, more importantly, on reducing its toxicity. Hence, the main objective of this study was to answer whether the degradation of a highly toxic compound of global concern for drinking water equals its detoxification. We, therefore, investigated the treatment of cylindrospermopsin (CYN) by •OH and SO4-• produced in Fenton and Fenton-like reactions. Although SO4-• radicals removed the toxin more effectively, both radical species substantially degraded CYN. The underlying degradation mechanisms were similar for both radical species and involved hydroxylation, dehydrogenation, decarboxylation, sulfate group removal, ring cleavage, and further fragmentation. The hydroxymethyl uracil and tricyclic guanidine moieties were the primary targets. Furthermore, the residual toxicity, assessed by a 3-dimensional human in vitro liver model, was substantially reduced during the treatment by both radical species. Although the results indicated that some of the formed degradation products might still be toxic, the overall reduction of the toxicity together with the proposed degradation pathways allowed us to conclude: “Yes, degradation of CYN equals its detoxification!”.

Investigation of the Phytochemical Composition, Antioxidant Activity, and Methylglyoxal Trapping Effect of Galega officinalis L. Herb In Vitro.

Galega officinalis L. has been known for centuries as an herbal medicine used to alleviate the symptoms of diabetes, but its comprehensive chemical composition and pharmacological activity are still insufficiently known. The current study involved the qualitative and quantitative phytochemical analysis and in vitro evaluation of the antioxidative and methylglyoxal (MGO) trapping properties of galega herb. Ultra high-performance liquid chromatography coupled with both the electrospray ionization mass spectrometer and diode-array detector (UHPLC-ESI-MS and UHPLC-DAD) were used to investigate the composition and evaluate the anti-MGO capability of extracts and their components. Hot water and aqueous methanol extracts, as well as individual compounds representing phytochemical groups, were also assessed for antioxidant activity using DPPH (2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl) and ABTS (2,2′-azino-bis(3-ethylbenz-thiazoline-6-sulfonic acid) assays. Quercetin and metformin were used as a positive control. We confirmed the presence of tricyclic quinazoline alkaloids, guanidines, flavonoids, and hydroxycinnamic acids (HCAs) in galega extracts. The polyphenolic fraction was dominated by mono-, di-, and triglycosylated flavonols, as well as monocaffeoylhexaric acids. The in vitro tests indicated which G. officinalis components exhibit beneficial antioxidative and MGO trapping effects. For galega extracts, flavonols, and HCAs, a potent antiradical activity was observed. The ability to trap MGO was noted for guanidines and flavonoids, whereas HCA esters and quinazoline alkaloids were ineffective. The formation of mono-MGO adducts of galegine, hydroxygalegine, and rutin in the examined water infusion was observed.

Decomposition products of cylindrospermopsin – a cyanotoxin produced by Raphidiopsis raciborskii (Woloszynska)

Abstract Toxins produced by cyanobacteria (cyanotoxins) and released into water have become a serious problem worldwide due to the increasing morbidity and mortality of living organisms they have caused. The ability to synthesize the cytotoxic alkaloid cylindrospermopsin (CYN) has been demonstrated in several freshwater species of cyanobacteria. CYN is highly chemically stable under environmental factors and decomposes only under alkaline conditions, where it forms derivatives. The toxicity potential of the decomposition products formed at pH 10 combined with high temperature (100°C) or UV-B irradiation (36 μmol m−2 s−1) has been research based on the crustacean Thamnocephalus platyurus (Thamnotoxkit FTM) and bacteria Vibrio fischeri (Deltatox® II) bioassays. This paper is a continuation and completion of our previous experiments and the obtained results showed that the applied conditions contributed to the decomposition of the CYN molecule to non-toxic products and its structural modifications by separating the uracil ring or/and the sulfate group from the tricyclic guanidine moiety, leading to a reduction in its toxicity. To the best of our knowledge, this is the first report describing the toxicity of CYN decomposition products formed under alkaline conditions combined with boiling temperature or UV-B irradiation.

Short Total Synthesis of [15N5]-Cylindrospermopsins from 15NH4Cl Enables Precise Quantification of Freshwater Cyanobacterial Contamination.

Fresh water cyanobacterial algal blooms represent a major health risk because these organisms produce cylindrospermopsin, a toxic, structurally complex, zwitterionic uracil-guanidine alkaloid recognized by the EPA as a dangerous drinking water contaminant. At present, the ability to detect and quantify the presence of cylindrospermospin in water samples is severely hampered by the lack of an isotopically labeled standard for analytical mass spectrometry. Herein, we present a concise, scaled total synthesis of 15N cylindrospermosin from 15N ammonium chloride, which leverages a unique stereoselective intramolecular double conjugate addition step to assemble the tricyclic guanidine core. In addition to providing the first pure isotopically labeled probe for precise quantification of this potent biotoxin in fresh water sources, our results demonstrate how unique constraints associated with isotope incorporation compel novel solutions to synthesis design.

Intramolecular Formation of Zwitterionic Intermediates in 1,3-Diaza-Claisen Rearrangements.

Isothioureas tethered to bridged-bicyclic tertiary allylic amines can be converted to carbodiimides through reaction with Hg(II) salts. Intramolecular cyclization of the tethered tertiary allylic amines to the carbodiimides afford zwitterionic intermediates that undergo 1,3-diaza-Claisen rearrangements, affording highly substituted tricyclic guanidines.

Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K As Anti-Malarial Agents.

The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q2 of 0.516. The model has predicted r2 of 0.91 showing that predicted IC50 values are in good agreement with experimental IC50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors.

Synthesis of Bicyclic and Tricyclic Chiral Guanidinium Salts by an Intramolecular Alkylation Approach

Synthetic studies leading to three new types of chiral guanidinium scaffolds are described. Structures of interest include bicyclic guanidine derivatives with various substitution patterns around the guanidine core, as well as a highly rigid tricyclic scaffold. The challenging targets were accessed by application of mercury(II)‐promoted guanylation of N‐Boc‐substituted thioureas and Ishikawa's desulfurative cyclization. In addition to our synthetic logics, a scalable synthesis of the tricyclic guanidinium salt is presented.

ChemInform Abstract: Netamines O—S, Five New Tricyclic Guanidine Alkaloids from the Madagascar Sponge Biemna laboutei, and Their Antimalarial Activities.

AbstractNetamines O (I) and Q (III) are found to be moderately cytotoxic, whereas Netamines O, P (IIa) and Q exhibit antiplasmodial activities.

Ozonation of Cylindrospermopsin (Cyanotoxin): Degradation Mechanisms and Cytotoxicity Assessments.

Cylindrospermopsin (CYN) is a potent toxic alkaloid produced by a number of cyanobacteria frequently found in lakes and reservoirs used as drinking water sources. We report for the first time detailed pathways for the degradation of CYN by treatment with ozone. This was accomplished by use of ultra-high-performance liquid chromatography (UHPLC)-quadrupole time-of-flight mass spectrometry (QTOF MS), which revealed that CYN is readily degraded by ozone with at least 36 transformation products. Structural similarities among the major products indicated that the carbon-carbon double bond in the uracil ring of CYN was most susceptible to attack by ozone. Furthermore, the nitrogen functionality associated with the tricyclic guanidine moiety is also involved via a degradation pathway that has not been previously observed. To assess the potential toxicity of ozonation products of CYN, the cytotoxicity of CYN and the mixture of its ozonation products was measured in a human hepatoma cell line (HepG2). The IC50 for CYN at 24 and 48 h incubations was approximately 64.1 and 12.5 μM, respectively; however, the ozonation products of CYN did not exhibit measurable cytotoxicity to human cells. The results indicate ozone is an effective and practical method for CYN attenuation in water treatment without formation of overtly toxic transformation products.

Netamines O-S, Five New Tricyclic Guanidine Alkaloids from the Madagascar Sponge Biemna laboutei, and Their Antimalarial Activities.

In our continuing program to isolate new compounds from the Madagascar sponge Biemna laboutei, five new tricyclic guanidine alkaloids, netamines O - S (1-5, resp.), have been identified together with the known compounds netamine E (6) and mirabilin J (7). The structures of all new netamines were assigned on the basis of spectroscopic analyses. Their relative configurations were established by analysis of ROESY data and comparison with literature data. Netamines O, P, and Q, which were isolated in sufficient quantities, were tested for their cytotoxic activities against KB cells and their activities against the malaria parasite Plasmodium falciparum. Netamines O and Q were found to be moderately cytotoxic. Netamines O, P, and Q exhibited antiplasmodial activities with IC₅₀ values of 16.99 ± 4.12, 32.62 ± 3.44, and 8.37 ± 1.35 μM, respectively.

Anti-parasitic Guanidine and Pyrimidine Alkaloids from the Marine Sponge Monanchora arbuscula

HPLC-UV-ELSD-MS-guided fractionation of the anti-parasitic extract obtained from the marine sponge Monanchora arbuscula, collected off the southeastern coast of Brazil, led to the isolation of a series of guanidine and pyrimidine alkaloids. The pyrimidines monalidine A (1) and arbusculidine A (7), as well as the guanidine alkaloids batzellamide A (8) and hemibatzelladines 9-11, represent new minor constituents that were identified by analysis of spectroscopic data. The total synthesis of monalidine A confirmed its structure. Arbusculidine A (7), related to the ptilocaulin/mirabilin/netamine family of tricyclic guanidine alkaloids, is the first in this family to possess a benzene ring. Batzellamide A (8) and hemibatzelladines 9-11 represent new carbon skeletons that are related to the batzelladines. Evaluation of the anti-parasitic activity of the major known metabolites, batzelladines D (12), F (13), L (14), and nor-L (15), as well as of synthetic monalidine A (1), against Trypanosoma cruzi and Leishmania infantum is also reported, along with a detailed investigation of parasite cell-death pathways promoted by batzelladine L (14) and norbatzelladine L (15).

Identification of TiO2 photocatalytic destruction byproducts and reaction pathway of cylindrospermopsin

Cylindrospermopsin (CYN) has become a significant environmental concern because of its extremely high toxicity and widespread distribution. TiO2 assisted photocatalytic degradation process has been proven to be effective for CYN degradation. However, the lack of investigation on byproducts and pathways of CYN photocatalytic destruction limited the assessment of this treatment technology (e.g. toxicity of effluent). Therefore, the reaction byproducts and pathways of CYN degradation by TiO2 photocatalysis were studied in this work by using high-performance liquid chromatography combined with quadrupole time-of-flight electrospray ionization tandem mass spectrometry (LC/Q-TOF–ESI–MS). The reaction pathways were proposed and discussed based on the detected byproducts and hydroxyl radical chemistry. The byproducts m/z 432.12 and 448.11 can be formed through hydroxylation by •OH hydrogen abstraction and addition to double bonds. Byproducts without the sulfate group can be generated through a sulfate elimination process. Byproducts (such as m/z 392.12 and 375.10) formed after ring opening by attacks on the hydroxymethyl uracil moiety and tricyclic guanidine moiety were also identified in this study. The detoxification study showed an effective removal of cytotoxicity after TiO2 photocatalytic treatment. This work is important in the proper assessment of the photocatalytic destruction of CYN in water and provides insights that can help determine the level of treatment required by such advanced oxidation technologies.

Tricyclic guanidine alkaloids from the marine sponge Acanthella cavernosa that stabilize the tumor suppressor PDCD4.

A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC50 values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions.

Kinetics and mechanisms of cylindrospermopsin destruction by sulfate radical-based advanced oxidation processes

Cylindrospermopsin (CYN) is a potent cyanobacterial toxin frequently found in water bodies worldwide raising concerns over the safety of drinking and recreational waters. A number of technologies have been investigated to remove and/or degrade cyanotoxins with advanced oxidation processes (AOPs) being among the most promising and effective for water detoxification. In this study, the degradation of CYN by sulfate radical-based UV-254 nm-AOPs was evaluated. The UV/S2O82− (UV/peroxydisulfate) was more efficient than UV/HSO5− (UV/peroxysulfate) and UV/H2O2 (UV/hydrogen peroxide) processes when natural water samples were used as reaction matrices. The observed UV fluence based pseudo-first-order rate constants followed the expected order of radical quantum yields. The presence of 200 μM natural organic matter (NOM) as carbon slightly inhibited the destruction of CYN; 1.24 mg L−1NO3− (nitrate) had no significant influence on the removal efficiency and 50 μg L−1 Fe2+ [iron (2+)] or Cu2+ [copper (2+)] improved the performance of UV/S2O82−. The addition of tert-butyl alcohol (t-BuOH; hydroxyl radical scavenger) in the reaction yielded byproducts that indicated specific sites in CYN preferentially attacked by sulfate radicals (SRs). The predominant CYN degradation byproduct was P448 consistent with fragmentation of the C5C6 bond of the uracil ring. The subsequent formation of P420 and P392 through a stepwise loss of carbonyl group(s) further supported the fragmentation pathway at C5C6. The byproduct P432 was identified exclusively as mono-hydroxylation of CYN at tricyclic guanidine ring, whereas P414 was detected as dehydrogenation at the tricyclic ring. The elimination of sulfate group and the opening of tricyclic ring were also observed. The possible degradation pathways of CYN by SR-AOP were presented.

Degradation Mechanism of Cyanobacterial Toxin Cylindrospermopsin by Hydroxyl Radicals in Homogeneous UV/H2O2 Process

The degradation of cylindrospermopsin (CYN), a widely distributed and highly toxic cyanobacterial toxin (cyanotoxin), remains poorly elucidated. In this study, the mechanism of CYN destruction by UV-254 nm/H2O2 advanced oxidation process (AOP) was investigated by mass spectrometry. Various byproducts identified indicated three common reaction pathways: hydroxyl addition (+16 Da), alcoholic oxidation or dehydrogenation (-2 Da), and elimination of sulfate (-80 Da). The initiation of the degradation was observed at the hydroxymethyl uracil and tricyclic guanidine groups; uracil moiety cleavage/fragmentation and further ring-opening of the alkaloid were also noted at an extended reaction time or higher UV fluence. The degradation rates of CYN decreased and less byproducts (species) were detected using natural water matrices; however, CYN was effectively eliminated under extended UV irradiation. This study demonstrates the efficiency of CYN degradation and provides a better understanding of the mechanism of CYN degradation by hydroxyl radical, a reactive oxygen species that can be generated by most AOPs and is present in natural water environment.

Synthesis, biological evaluation and molecular docking studies of tricyclic guanidine derivatives for anti-malarial activity

IntroductionMalaria is the most lethal among the parasitic diseases and challenge for developing counties. Globally, an estimated 3.3 billion people were at risk of malaria in 2011, with populations living in sub-Saharan Africa having the highest risk of acquiring malaria. Malarial infection caused by P. falciparum is the most deadly form among all pathogens. Moreover, there has been rapid increase in resistance to drugs by P. falciparum. This resistance is considered because of emergence through mutation or biochemical changes in the active site of drug targets. The lactate dehydrogenase of P. falciparum (PfLDH) has been used since long time as a potential molecular drug target for malaria. The LDH plays role in the inter-conversion of pyruvate to lactate in the glycolysis cycle, which is required for energy production in living cells. Objectives1) Synthesis of tricyclic guanidine derivatives and biological evaluation against resistant strain of P. falciparum (Lactate Dehydrogenase Inhibitor). 2) Molecular docking of synthesized derivatives to understand mechanism of inhibition. MethodsWe have synthesized fifty tricyclic guanidine derivatives based on batzelladine K backbone. All synthesized compounds were evaluated for anti-malarial activity against chloroquine resistant strains of P. falciparum by using plasmodial LDH activity as measure of inhibition. To understand the mechanism of inhibition and to identify pharmacophore required for activity, the molecular docking of tricyclic guanidine compounds was performed using CDOCKER program in Discovery Studio suit 3.5. Results & DiscussionWe have obtained many potent inhibitors. The docking studies showed that there is very strong correlation between in silico and in vitro results. The most active compound was found to have least CDOCKER interaction energy (–43.25 kcal/mol). It showed hydrophobic interaction with Gly27, Ala98, Asp53 and Ile54 residues in the enzyme binding pocket similar to that of chloroquine. ConclusionThe synthesized derivatives are potent inhibitor of chloroquine-resistant PfLDH and act on same binding site to that of chloroquine. Based on these results, more potent inhibitor against P. falciparum can be designed.

Bismuth oxybromide promoted detoxification of cylindrospermopsin under UV and visible light illumination

Bismuth oxybromide (BiOBr) was prepared and characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS) and UV–vis diffuse reflectance spectroscopy (DRS). The BiOBr promoted detoxification of cylindrospermopsin (CYN) under UV (λ<350nm) and visible light (λ>420nm) illumination was studied. The results revealed that the toxic uracil unit of CYN was removed, and the carboxylic group of the degraded product was also decomposed, to give the innoxious tricyclic guanidine product under the title conditions. In contrast, the traditional Fenton reagents (Fe2+ and H2O2) limited to remove the uracil moiety of CYN with the carboxylic group intact. Presumably, the decarboxylation ability of BiOBr was induced by Br 4p valence band hole (hBr4p+), and the degradation mechanism was also proposed based on the experimental results and theoretical calculation.

Desymmetrization of meso-2,5-diallylpyrrolidinyl ureas through asymmetric palladium-catalyzed carboamination: stereocontrolled synthesis of bicyclic ureas.

Desymmetrization of meso-2,5-diallylpyrrolidinyl ureas through asymmetric palladium-catalyzed carboamination: stereocontrolled synthesis of bicyclic ureas.

Synthesis and Biological Evaluation of Tricyclic Guanidine Analogues of Batzelladine K for Antimalarial, Antileishmanial, Antibacterial, Antifungal, and Anti‐HIV Activities

Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV-1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine-sensitive D6 strain with IC(50) 1.25 and 0.88 μM and chloroquine-resistant W2 strain with IC(50) 1.64 and 1.07 μM, respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC(50) 2.39 and 2.78 μM and IC(90) 11.27 and 12.76 μM, respectively. Three analogues 12c, 14c, and 14i were the most active against various pathogenic bacteria and fungi with IC(50) < 3.02 μM and MIC/MBC/MFC <6 μM. Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV-1. Our study demonstrated that the tricyclic guanidine compounds provide new structural class for broad spectrum activity.