Guanidine Alkaloids Research Articles

Monanchoxymycalins A and B, New Hybrid Pentacyclic Guanidine Alkaloids from the Far-Eastern Marine Sponge Monanchora pulchra

The new pentacyclic guanidine alkaloids, monanchoxymycalin A (1) and monanchoxymycalin B (2) were isolated from the Far-Eastern marine sponge Monanchora pulchra. Their structures were assigned on the basis of detailed analysis of lD- and 2D-NMR spectroscopic and mass spectrometric data. Compounds 1 and 2 exhibited potent cytotoxic activities against cervical epithelioid carcinoma HeLa cells and breast adenocarcinoma MDA-MB231 cells.

Marine guanidine alkaloids crambescidins inhibit tumor growth and activate intrinsic apoptotic signaling inducing tumor regression in a colorectal carcinoma zebrafish xenograft model.

The marine environment constitutes an extraordinary resource for the discovery of new therapeutic agents. In the present manuscript we studied the effect of 3 different sponge derived guanidine alkaloids, crambescidine-816, -830, and -800. We show that these compounds strongly inhibit tumor cell proliferation by down-regulating cyclin-dependent kinases 2/6 and cyclins D/A expression while up-regulating the cell cyclin-dependent kinase inhibitors -2A, -2D and -1A. We also show that these guanidine compounds disrupt tumor cell adhesion and cytoskeletal integrity promoting the activation of the intrinsic apoptotic signaling, resulting in loss of mitochondrial membrane potential and concomitant caspase-3 cleavage and activation. The crambescidin 816 anti-tumor effect was fnally assayed in a zebrafish xenotransplantation model confirming its potent antitumor activity against colorectal carcinoma in vivo.Considering these results crambescidins could represent promising natural anticancer agents and therapeutic tools.

Mellpaladines and dopargimine, novel neuroactive guanidine alkaloids from a Palauan Didemnidae tunicate

Novel guanidine alkaloids dopargimine (1) and mellpaladines A–C (2–4) were isolated from a Palauan Didemnidae tunicate. The structures of 1–4 were elucidated on the basis of spectral data along with chemical reactions. A putative biosynthetic building block of 1–4, 4-guanidinobutyric acid (5), and dimeric polysulfur dopamine, as well as lissoclibadins 11 (6a) and 12 (6b) were also isolated. Compounds 1–3 bound to synaptic receptors, and modulated behavioral profiles of mice after intracerebroventricular injection.

Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes.

Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism.

Absolute Configuration and Body Part Distribution of the Alkaloid 6-epi-Monanchorin from the Marine Polychaete Chaetopterus variopedatus

As a result of the first study on secondary metabolites from the cosmopolitan bioluminescent marine tube polychaete Chaetopterus variopedatus, a new bicyclic guanidine alkaloid, 6-epi-monanchorin (1), along with the previously known monanchorin (2) were isolated. The structure of 1 was elucidated by spectroscopic and chemical methods, including a cleavage of the C₁-0₇ bond to obtain a secondary alcohol (3), which was used to determine the absolute configurations by Mosher's method. It was found that 1 and 2 were mainly accumulated in a secreted mucus special organ of the worm (food net), where green and blue-green microalgae were detected. A biosynthetic pathway to 6-epi-monanchorin and monanchorin from dietary polyeic fatty acid precursors was proposed.

Protective effects of Solanum cernuum extract against chromosomal and genomic damage induced by methyl methanesulfonate in Swiss mice.

Solanum cernuum Vell is a Brazilian shrub or small tree, restricted to Southeast states of the country. The leaves are commercialized as "panacéia" and indicated for the treatment of urinary disorders, gonorrhea, scabies, skin diseases and as desobstruent, diuretic and antiarrhythmic. The hydroalcholic extract is active in the treatment of gastric ulcer. The aim of this study was to evaluate the genotoxic and antigenotoxic potential of S. cernuum hydroalcoholic extract (SC) in Swiss mice by micronucleus and comet assays. The animals were treated by gavage with the doses of 500, 1000 and 2000mg/kg body weight (b.w.). For antigenotoxicity assessment, the doses of 15, 30, 60, 120 and 240mg/kg b.w SC were administered simultaneously with the mutagen methyl methanesulfonate (MMS, 40mg/kg b.w., i.p.). The results showed that the SC was not genotoxic in both micronucleus and comet assays. On the other hand, the treatment with the lowest dose of SC (15mg/kg b.w.) plus MMS showed a statistically significant reduction in the frequency of micronuclei compared to treatment only with MMS. For the comet assay, significant reduction in extensions of DNA damage was observed in all treatments with SC combined with MMS in comparison with only MMS. The antigenotoxic activity observed for the SC may be due to the antioxidant potential of the compounds present in the extract such as guanidine alkaloids and flavonoids.

Guanidine Alkaloids from the Marine Sponge Monanchora pulchra Show Cytotoxic Properties and Prevent EGF-Induced Neoplastic Transformation in Vitro.

Guanidine alkaloids from sponges Monanchora spp. represent diverse bioactive compounds, however, the mechanisms underlying bioactivity are very poorly understood. Here, we report results of studies on cytotoxic action, the ability to inhibit EGF-induced neoplastic transformation, and the effects on MAPK/AP-1 signaling of eight rare guanidine alkaloids, recently isolated from the marine sponge Monanchora pulchra, namely: monanchocidin A (1), monanchocidin B (2), monanchomycalin C (3), ptilomycalin A (4), monanchomycalin B (5), normonanchocidin D (6), urupocidin A (7), and pulchranin A (8). All of the compounds induced cell cycle arrest (apart from 8) and programmed death of cancer cells. Ptilomycalin A-like compounds 1–6 activated JNK1/2 and ERK1/2, following AP-1 activation and caused p53-independent programmed cell death. Compound 7 induced p53-independent cell death without activation of AP-1 or caspase-3/7, and the observed JNK1/2 activation did not contribute to the cytotoxic effect of the compound. Alkaloid 8 induced JNK1/2 (but not ERK1/2) activation leading to p53-independent cell death and strong suppression of AP-1 activity. Alkaloids 1–4, 7, and 8 were able to inhibit the EGF-induced neoplastic transformation of JB6 P+ Cl41 cells. Our results suggest that investigated guanidine marine alkaloids hold potential to eliminate human cancer cells and prevent cancer cell formation and spreading.

Cytotoxic Guanidine Alkaloids from a French Polynesian Monanchora n. sp. Sponge.

Four bicyclic and three pentacyclic guanidine alkaloids (1-7) were isolated from a French Polynesian Monanchora n. sp. sponge, along with the known alkaloids monalidine A (8), enantiomers 9-11 of known natural product crambescins, and the known crambescidins 12-15. Structures were assigned by spectroscopic data interpretation. The relative and absolute configurations of the alkaloids were established by analysis of (1)H NMR and NOESY spectra and by circular dichroism analysis. The new norcrambescidic acid (7) corresponds to interesting biosynthetic variation within the pentacyclic core. All compounds exhibited antiproliferative and cytotoxic efficacy against KB, HCT116, HL60, MRC5, and B16F10 cancer cells, with IC50 values ranging from 4 nM to 10 μM.

Polycyclic Guanidine Alkaloids from Poecilosclerida Marine Sponges.

Sessile marine sponges provide an abundance of unique and diversified scaffolds. In particular, marine guanidine alkaloids display a very wide range of biological applications. A large number of cyclic guanidine alkaloids, including crambines, crambescins, crambescidins, batzelladines or netamins have been isolated from Poecilosclerida marine sponges. In this review, we will explore the chemodiversity of tri- and pentacyclic guanidine alkaloids. NMR and MS data tools will also be provided, and an overview of the wide range of bioactivities of crambescidins and batzelladines derivatives will be given.

Haliclonadiamine Derivatives and 6-epi-Monanchorin from the Marine Sponge Halichondria panicea Collected at Iriomote Island.

Four new haliclonadiamine analogues, (10Z,12E)-haliclonadiamine (1), (10E,12Z)-haliclonadiamine (2), and halichondriamines A (3) and B (4), were isolated from the Okinawan marine sponge Halichondria panicea together with haliclonadiamine (5) and papuamine (6). The structures of 1-4 were elucidated on the basis of their spectroscopic data by comparisons with those for 5 and 6. Further separation of the remaining fraction led to the isolation of a new bicyclic guanidine alkaloid, 6-epi-monanchorin (7), along with monanchorin (8). Compound 7 is the epimer of 8 at the 6 position. Compounds 1-6 inhibited the growth of Mycobacterium smegmatis with inhibition zones of 12, 7, 8, 7, 16, and 12 mm at 10 μg/disc, respectively. Compounds 2-4 exhibited weak cytotoxicities against the Huh-7 (hepatoma) human cancer cell line and were 2-fold less active than 5 and 6. Compounds 7 and 8 were not active against M. smegmatis at 20 μg/disc or the cancer cell line at 10 μM.

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.

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.

De Novo Asymmetric Synthesis of (+)-Monanchorin.

A de novo asymmetric total synthesis of the guanidine alkaloid natural product (+)-monanchorin has been achieved in nine steps from the commodity chemicals furan and caproic acid. The asymmetry of the route was introduced by a Noyori reduction of an acylfuran. In addition, this route relies upon an Achmatowicz rearrangement, a diastereoselective palladium catalyzed glycosylation, reductive amination, and an acid catalyzed bicyclic guanidine mixed acetal formation.

Crambescin C1 Exerts a Cytoprotective Effect on HepG2 Cells through Metallothionein Induction.

The Mediterranean marine sponge Crambe crambe is the source of two families of guanidine alkaloids known as crambescins and crambescidins. Some of the biological effects of crambescidins have been previously reported while crambescins have undergone little study. Taking this into account, we performed comparative transcriptome analysis to examine the effect of crambescin-C1 (CC1) on human tumor hepatocarcinoma cells HepG2 followed by validation experiments to confirm its predicted biological activities. We report herein that, while crambescin-A1 has a minor effect on these cells, CC1 protects them against oxidative injury by means of metallothionein induction even at low concentrations. Additionally, at high doses, CC1 arrests the HepG2 cell cycle in G0/G1 and thus inhibits tumor cell proliferation. The findings presented here provide the first detailed approach regarding the different effects of crambescins on tumor cells and provide a basis for future studies on other possible cellular mechanisms related to these bioactivities.

New Derivatives of Natural Acyclic Guanidine Alkaloids with TRPV Receptor-Regulating Properties

The guanidine alkaloids, dihydropulchranin A (2), prepared from pulchranin A from the sponge Monanchora pulchra, and hexadecylguanidine (3), a synthetic analog of pulchranins, were studied for their TRPV channel-regulating activities. Compound 2 was active as an inhibitor of rTRPV1 and hTRPV3 receptors with EC50 values of 24.3 and 59.1 μM, respectively. Hexadecylguanidine (3) was not active against these receptors.

Human ABCB1 confers cells resistance to cytotoxic guanidine alkaloids from Pterogyne nitens.

Multidrug resistance (MDR) caused by human ABCB1 (P-glycoprotein/MDR1) is one of the major obstacles in chemotherapy. To understand the mechanism of MDR by ABCB1 and circumvent the MDR, in the present study, we established human ABCB1-expressing cells (Flp-In-293/ABCB1 cells) and examined the cytotoxic effects of four guanidine alkaloids from Pterogyne nitens (galegine, nitensidine A, pterogynidine and pterogynine) using Flp-In-293/Mock and Flp-In-293/ABCB1 cells. The activity of ABCB1 in Flp-In-293/ABCB1 cells were confirmed by typical substrates for ABCB1 (taxol and vinblastine) in MTT assay. Flp-In-293/ABCB1 cells were also resistant to the four guanidine alkaloids as well as taxol and vinblastine compared to Flp-In-293/Mock cells although the four guanidine alkaloids exhibited cytotoxicity against the two Flp-In-293 cells. Furthermore, the four guanidine alkaloids were also found to stimulate the ATPase activity of ABCB1 in ATPase assays. These results suggest that ABCB1 can confer the resistance to the cytotoxic guanidine alkaloids by transporting them.

Normonanchocidins A, B and D, New Pentacyclic Guanidine Alkaloids from the Far-Eastern Marine Sponge Monanchora pulchra

New pentacyclic guanidine alkaloids, normonanchocidins A, B and D (1-3) along with the earlier known monanchocidin A were isolated from the Far-Eastern marine sponge Monanchora pulchra. Structures of 1-3 were elucidated using ID- and 2D-NMR spectroscopic and mass spectrometric data. Compound 1 and a mixture of 2 and 3 (1:1) exhibited cytotoxic activities against human leukemia THP-1 cells with IC50 values of 2.1 μM and 3.7 μM, respectively, and against cervix epithelial carcinoma HeLa cells with IC50 of 3.8 μM and 6.8 μM, respectively.

ChemInform Abstract: First Total Synthesis of a Guanidine Alkaloid Nitensidine D Using Immobilized Ionic Liquid, Microwaves and Formamidinesulfinic Acid.

AbstractA total synthesis of the guanidine alkaloid nitensidine D (I) is reported, which uses geraniol as starting material.

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).

Ecliptamines A–D, four new guanidine alkaloids from Eclipta prostrata L.

Four structurally unique guanidine alkaloids ecliptamines A–D (1–4) and one known analog (5) were isolated from the aerial parts of Eclipta prostrata (Asteraceae). Their structures were elucidated on the basis of spectroscopic analyses and chemical methods. The inhibitory activities of 1, 2 and 5 were assayed with respect to cyclooxygenase-1 (COX-1) and -2 (COX-2). Compound 5 showed moderate inhibitory activities against COX-1 and -2 with IC50 values of 3.0×10−3M and 8.3×10−4M, respectively, whereas aspirin as a positive control displayed the IC50 values of 4.2×10−4M (against COX-1) and 7.1×10−4M (against COX-2).