Guanidine Alkaloids Research Articles

First total synthesis of a guanidine alkaloid Nitensidine D using immobilized ionic liquid, microwaves and formamidinesulfinic acid

An efficient first total synthesis of a naturally occurring guanidine alkaloid, Nitensidine D isolated from ethanol extract of Pterogyne nitens has been described. Geraniol has been used as the starting material. N-alkylation of phthalimide has been achieved using immobilized ionic liquid and formamidinesulfinic acid acts as the guanylating reagent. First total synthesis of Nitensidine D is described.

Isolation and chacarterization of a new anti-trypanosomal guanidine alkaloid from Alchornea glandulosa (Euphorbiaceae)

Bioactivity-guided fractionation of MeOH extract from leaves of Alchornea glandulosa Poepp. (Euphorbiaceae) afforded a new guanidine alkaloid named alchornedine. Its structure, which displayed a very rare ring system, was elucidated based on NMR, IR and MS spectral analysis. Alchornedine displayed an antiprotozoal activity against Trypanosoma cruzi (Y strain). By using the MTT assay, the trypomastigotes showed an IC50 value of 92.54 µg/mL (442.8µM), a similar effectiveness to the standard drug benznidazole. Alchornedine showed a promising activity against the intracellular amastigotes, with an IC50 value of 27.17 µg/mL (129.1µM). Considering benznidazole as standard drug, this guanidine alkaloid was approximately 3-fold more effective against the intracellular form of T. cruzi. The mammalian cytotoxicity of alchornedine was verified against NCTC cells and demonstrated an IC50 of 49.62 µg/mL (237.4µM), but the compound demonstrated a selective elimination of parasites inside macrophages, without affecting the morphology of host cells. Alchornedine was effective against both clinical forms of T. cruzi and could be used as a scaffold for future drug design studies against American Trypanosomiais.

Alchornedine, a new anti-trypanosomal guanidine alkaloid from Alchornea glandulosa.

Bioactivity-guided fractionation of the MeOH extract from the leaves of Alchornea glandulosa afforded a new guanidine alkaloid named alchornedine, as well as two other inactive derivatives (pteroginine and pteroginidine). The structure of alchornedine, which shows a very rare ring system, was elucidated based on NMR, IR, and MS spectral analyses. This compound displayed antiprotozoal activity against Trypanosoma cruzi (Y strain). By using the MTT assay, the trypomastigotes showed an IC50 value of 93 µg/mL (443 µM), a similar effectiveness to the standard drug benznidazole. Alchornedine also showed activity against the intracellular amastigotes, with an IC50 value of 27 µg/mL (129 µM). Using benznidazole as a standard drug, this guanidine alkaloid was approximately 3-fold more effective against the intracellular form of T. cruzi. The mammalian cytotoxicity of alchornedine was verified against NCTC cells and demonstrated an IC50 of 50 µg/mL (237 µM), but this compound demonstrated a selective elimination of parasites inside macrophages without affecting the morphology of the host cells. Alchornedine was effective against both clinical forms of T. cruzi and could be used as a scaffold for future drug design studies against American trypanosomiasis.

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.

In Vitro Antibacterial Activity of Prenylated Guanidine Alkaloids from Pterogyne nitens and Synthetic Analogues.

The present investigation deals with the antibiotic activity of eight natural guanidine alkaloids and two synthetic analogues against a variety of clinically relevant methicillin-resistant Staphylococcus aureus strains. Galegine (1) and pterogynidine (2) were the most potent compounds, with a minimum inhibitory concentration of 4 mg/L, to all tested strains. The preliminary chemical features correlating to anti-MRSA activity showed that the size of the side chain and the substitution pattern in the guanidine core played a key role in the antibacterial activity of the imino group. Guanidine alkaloids 1 and 2 are promising molecular models for further synthetic derivatives and, thus, for medicinal chemistry studies.

Environmental solutions for the sustainable production of bioactive natural products from the marine sponge Crambe crambe

Crambe crambe is a Mediterranean marine sponge known to produce original natural substances belonging to two families of guanidine alkaloids, namely crambescins and crambescidins, which exhibit cytotoxic and antiviral activities. These compounds are therefore considered as potential anticancer drugs. The present study focuses on the environmental assessment of a novel in vivo process for the production of pure crambescin and crambescidin using sponge specimens cultured in aquarium.The assessment was performed following the ISO 14040 standard and extended from the production of the different mass and energy flows to the system to the growth of the sponge in indoor aquarium and further periodic extraction and purification of the bioactive compounds. According to the results, the two stages that have a remarkable contribution to all impact categories are the purification of the bioactive molecules followed by the maintenance of the sponge culture in the aquarium. Among the involved activities, the production of the chemicals (particularly methanol) together with the electricity requirements (especially due to the aquarium lighting) are responsible for up to 90% of the impact in most of the assessed categories. However, the contributions of other stages to the environmental burdens, such as the collection of sponges, considerably depend on the assumptions made during the inventory stage. The simulation of alternative scenarios has led to propose improvement alternatives that may allow significant reductions ranging from 20% to 70%, mainly thanks to the reduction of electricity requirements as well as the partial reuse of methanol.

Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1

The Pterogyne nitens (Fabaceae) tree, native to South America, has been found to produce guanidine alkaloids as well as bioactive flavonols such as kaempferol, quercetin, and rutin. In the present study, we examined the possibility of interaction between human ATP-binding cassette (ABC) transporter ABCB1 and four guanidine alkaloids isolated from P. nitens (i.e., galegine, nitensidine A, pterogynidine, and pterogynine) using human T cell lymphoblast-like leukemia cell line CCRF-CEM and its multi-drug resistant (MDR) counterpart CEM/ADR5000. In XTT assays, CEM/ADR5000 cells were resistant to the four guanidine alkaloids compared to CCRF-CEM cells, although the four guanidine alkaloids exhibited some level of cytotoxicity against both CCRF-CEM and CEM/ADR5000 cells. In ATPase assays, three of the four guanidine alkaloids were found to stimulate the ATPase activity of ABCB1. Notably, nitensidine A was clearly found to stimulate the ATPase activity of ABCB1 as strongly as the control drug, verapamil. Furthermore, the cytotoxic effect of nitensidine A on CEM/ADR5000 cells was synergistically enhanced by verapamil. Nitensidine A inhibited the extrusion of calcein by ABCB1. In the present study, the possibility of interaction between ABCB1 and two synthetic nitensidine A analogs (nitensidine AT and AU) were examined to gain insight into the mechanism by which nitensidine A stimulates the ATPase activity of ABCB1. The ABCB1-dependent ATPase activity stimulated by nitensidine A was greatly reduced by substituting sulfur (S) or oxygen (O) for the imino nitrogen atom (N) in nitensidine A. Molecular docking studies on human ABCB1 showed that, guanidine alkaloids from P. nitens dock to the same binding pocket as verapamil. Nitensidine A and its analogs exhibit similar binding energies to verapamil. Taken together, this research clearly indicates that nitensidine A is a novel substrate for ABCB1. The present results also suggest that the number, binding site, and polymerization degree of the isoprenyl moiety in the guanidine alkaloids and the imino nitrogen atom cooperatively contribute to their stimulation of ABCB1's ATPase activity.

Monanchomycalin C, a New Pentacyclic Guanidine Alkaloid from the Far-Eastern Marine Sponge Monanchora Pulchra

A new pentacyclic guanidine alkaloid, monanchomycalin C (1), along with the earlier known ptilomycalin A (2), were isolated from the Far-Eastern marine sponge Monanchora pulchra. The structure of 1 was elucidated using 1D and 2D NMR spectroscopic and ma ss spectrometric da ta. Compounds 1 and 2 exhibited cytotoxic activities against human breast cancer MDA-MB-231 cells with IC50 values of 8.2 microM and 4.3 pM, respectively.

A single betaproteobacterium dominates the microbial community of the crambescidine-containing sponge Crambe crambe

Crambe crambe is a marine sponge that produces high concentrations of the pharmacologically significant pentacyclic guanidine alkaloids (PGAs), Crambescines and Crambescidines. Although bio-mimetic chemical synthesis of PGAs suggests involvement of microorganisms in their biosynthesis, there are conflicting reports on whether bacteria are associated with this sponge or not. Using 16S rRNA gene pyrosequencing we show that the associated bacterial community of C. crambe is dominated by a single bacterial species affiliated to the Betaproteobacteria. Microscopy analysis of sponge tissue sections using a specific probe and in situ hybridization confirmed its dominance in the sponge mesohyl and a single microbial morphology was observed by transmission electron microscopy. If confirmed the presence of a simple bacteria community in C. crambe makes this association a very pertinent model to study sponge-bacteria interactions and should allow further research into the possible implication of bacteria in PGA biosynthesis.

Pulchranins B and C, New Acyclic Guanidine Alkaloids from the Far-Eastern Marine Sponge Monanchora Pulchra

New marine natural products, pulchranins B and C (2 and 3), were isolated from the marine sponge Monanchora pulchra and their structures were established using NMR and MS analysis. Compounds 2 and 3 were moderately active as inhibitors of TRPV1 (EC50 value of 95 and 183 microM, respectively) and less potent against TRPV3 and TRPA1 receptors.

Oxidative stress induced in Leishmania infatum by batzelladine L and norbatzelladine L alkaloids isolated from the marine sponge Monanchora arbuscula[manuell

Leishmaniasis and American Trypanosomiais are protozoan neglected diseases affecting about 12 and 28 million people yearly in developing countries, respectively, with few and toxic alternatives for treatment. The study of new cell death pathways in protozoan parasites is an important strategy to control the progress of infectious diseases. In the search towards new drug leads to treat parasitic infectious diseases, marine natural products are considered promising tools for the discovery of drug prototypes. In the present investigation, the alkaloids batzelladine L and norbatzelladine L, isolated from the marine sponge Monanchora arbuscula, were tested against Leishmania infantum and T. cruzi parasites. Both alkaloids displayed IC50 in the range between 1 to 4 µg/mL, with an IC50 against a mammalian cell in the range between of 13 to 44 µg/mL. Batzelladine L and norbatzelladine L altered the permeability of Leishmania plasma membrane, but norbatzelladine L induced a time-dependent and the highest penetration of the fluorescent dye SYTOX Green. Both batzelladine L and norbatzelladine L induced rapid depolarization of Leishmania mitochondrial membrane potential, resulting in an up-regulation of reactive oxygen species (ROS), leading to oxidative stress. Moreover, batzelladine L demonstrated the highest capacity to induce ROS production, in a 4,300-fold higher levels when compared to untreated parasites. Flow cytometry analysis demonstrated an intense exposure of phospatidylserine in the outer leaflet of plasma membrane of batzelladine L-treated parasites. The size of the side alkyl chain of the two guanidine alkaloids batzelladine L and norbatzelladine L seems to play a major role in the antiparasitic effect. Both alkaloids represent promising tools to study novel cellular death pathways in Leishmania parasites.

Nitensidine A, a guanidine alkaloid from Pterogyne nitens, induces osteoclastic cell death

Nitensidine A is a guanidine alkaloid isolated from Pterogyne nitens, a common plant in South America. To gain insight into the biological activity of P. nitens-produced compounds, we examined herein their biological effects on osteoclasts, multinucleated giant cells that regulate bone metabolism by resorbing bone. Among four guanidine alkaloids (i.e., galegine, nitensidine A, pterogynidine, and pterogynine), nitensidine A and pterogynine exhibited anti-osteoclastic effects at 10μM by reducing the number of osteoclasts on the culture plate whereas galegine and pterogynidine did not. The anti-osteoclastic activities of nitensidine A and pterogynine were exerted in a concentration-dependent manner, whereas nitensidine A exhibited an approximate threefold stronger effect than pterogynine (IC50 values: nitensidine A, 0.93±0.024μM; pterogynine, 2.7±0.40μM). In the present study, the anti-osteoclastic effects of two synthetic nitensidine A derivatives (nitensidine AT and AU) were also examined to gain insight into the structural features of nitensidine A that exert an anti-osteoclastic effect. The anti-osteoclastic effect of nitensidine A was greatly reduced by substituting the imino nitrogen atom in nitensidine A with sulfur or oxygen. According to the differences in chemical structures and anti-osteoclastic effects of the four guanidine alkaloids and the two synthetic nitensidine A derivatives, it is suggested that the number, binding site, and polymerization degree of isoprenyl moiety in the guanidine alkaloids and the imino nitrogen atom cooperatively contribute to their anti-osteoclastic effects.

Guanidine Alkaloids from Plumbago zeylanica

Eleven new guanidine alkaloids, plumbagines A-G (2-8) and plumbagosides A-D (9-12), as well as two known analogues (1, 13), were isolated from the aerial parts of Plumbago zeylanica. Their structures were elucidated by spectroscopic analyses including 1D and 2D NMR, MS, IR, and CD methods. The absolute configuration of 1 was determined by single-crystal X-ray diffraction of its derivative (1a).

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.

ChemInform Abstract: Palladium‐Mediated Total Synthesis of Bioactive Natural Products

AbstractReview: ca. 300 refs.

New Antibacterial Germacrene from Verbesina negrensis

Several health benefits have been attributed to members of the Verbesina genus, including promotion of urinary and gastrointestinal health. Verbesina species are also reported to exhibit antibacterial, antiparasitic, and antioxidant activities. Although members of the Verbesina genus produce various pharmacologically relevant chemicals as secondary metabolites, including eudesmanes, flavonoids, guanidine alkaloids, acetylenic compounds, and germacrenes, the active compounds required for these benefits remain unknown. To investigate potential antimicrobial activities of Verbesina negrensis, crude extracts from plant aerial structures were evaluated. Following chemical fractionation, the chloroformic extract from Verbesina negrensis was subjected to bioassay-guided isolation using disk diffusion assays to determine antimicrobial activity. The active compound was characterized as 6β-cinnamoyloxy-1β-hydroxy-10α-metoxy-3-oxo-germacra-4,5Z-ene (1). Fractions containing 1 inhibited both Enterococcus faecalis (ATCC 29 212) and Staphylococcus aureus (ATCC 29213). The MIC for 1 was determined by microbroth dilution assay to be 64 µg/mL for both E. faecalis and S. aureus.

Chemical and Biological Aspects of the Genus Verbesina

The current paper reviews the published literature up to March 2012 regarding the phytochemical components and biological activities of Verbesina species (Asteraceae). A compilation of compounds isolated from several members of this genus is presented. Eudesmanes are the most common secondary metabolites found within this genus. Flavonoids, guanidine alkaloids, acetylenic compounds, and several other terpenes with a great variety of hydrocarbon skeletons have also been isolated. The botanical classification, ethnopharmacology and pharmacological applications of Verbesina species are discussed. Keywords: Antihypertensive, asteraceae (compositae), eudesmanes, guanidine alkaloids, verbesina, terpenoids.

Palladium-Mediated Total Synthesis of Bioactive Natural Products

The search for efficient synthetic procedures for natural products, drugs, and materials with economical and ecological advantages is an important area of current interst in synthetic organic chemistry. We have made an attempt to summarize the progress made in this area since 2005. This article describes the syntheses of several natural products and drugs that employ multiple palladium-catalyzed processes in either a sequential or a domino fashion. 1 Introduction 2 Palladium-Mediated Synthesis of Alkaloids 2.1 Indole Alkaloids 2.2 Carbazole Alkaloids 2.3 Quinoline and Isoquinoline Alkaloids 2.4 Pyrrole and Pyridine Alkaloids 2.5 Pyrrolizidine and Indolizidine Alkaloids 2.6 Imidazole and Guanidine Alkaloids 2.7 Other Alkaloids 3 Palladium-Mediated Synthesis of Natural Products Containing a Sugar Moiety 4 Palladium-Mediated Synthesis of Marine Natural Products 5 Palladium-Mediated Synthesis of Amino Acids and Peptides 6 Palladium-Mediated Synthesis of Terpenoids 7 Miscellaneous Natural Products 8 Conclusion

P03.04 - Marine Alkaloid Monanchocidin: A Proteomic-Based Screening of Protein Targets in Cisplatin-Resistant Tumor Cells

Marine sponges are a rich source of natural compounds that possess potent anticancer activities. In continuation of our research of anticancer marine sponge metabolites, we investigated the new guanidine alkaloid monanchocidin, recently isolated by us from the sponge Monanhora pulchra [1, 2]. We have shown the substance to posses equal levels of cytotoxicity in vitro against a cisplatin-sensitive human embryonal carcinoma cell line, NTERA2, and NTERA2-R, a cisplatin-resistant subline derived from this cell line.

Differential Effects of Crambescins and Crambescidin 816 in Voltage-Gated Sodium, Potassium and Calcium Channels in Neurons

Crambescins and crambescidins are two families of guanidine alkaloids from the marine sponge Crambe crambe. Although very little information about their biological effect has been reported, it is known that crambescidin 816 (Cramb816) blocks calcium channels in a neuroblastoma X glioma cell line. Taking this into account, and the fact that ion channels are frequent targets for natural toxins, we examined the effect of Cramb816 and three compounds from the crambescin family, norcrambescin A2 (NcrambA2), crambescin A2 (CrambA2), and crambescin C1 (CrambC1), in the main voltage-dependent ion channels in neurons: sodium, potassium, and calcium channels. Electrophysiological recordings of voltage gated sodium, potassium, and calcium currents, in the presence of these guanidine alkaloids, were performed in cortical neurons from embryonic mice. Different effects were discovered: crambescins inhibited K(+) currents with the following potency: NcrambA2 > CrambC1 > CrambA2, while Cramb816 lacked an effect. Only CrambC1 and Cramb816 partially blocked Na(+) total current. However, Cramb816 partially blocked Ca(2+) , while NcrambA2 did not. Since the blocking effect of Cramb816 on calcium currents has not been previously reported in detail, we further pharmacologically isolated the two main fractions of HVA Ca(2+) channels in neurons and investigated the Cramb816 effect on them. Here, we revealed that Cav1 or L-type calcium channels are the main target for Cramb816. These two families of guanidine alkaloids clearly showed a structure-activity relationship with the crambescins acting on voltage-gated potassium channels, while Cramb816 blocks the voltage-gated calcium channel Cav1 with higher potency than nifedipine. The novel evidence that Cramb816 partially blocked CaV and NaV channels in neurons suggests that this compound might be involved in decreasing the neurotransmitter release and synaptic transmission in the central nervous system. The findings presented here provide the first detailed approach on the different effects of crambescin and crambescidin compounds in voltage-gated sodium, potassium, and calcium channels in neurons and thus provide a basis for future studies.