Pentacyclic Guanidine Alkaloids Research Articles

Marine alkaloid monanchoxymycalin C: a new specific activator of JNK1/2 kinase with anticancer properties

Monanchoxymycalin C (MomC) is a new marine pentacyclic guanidine alkaloid, recently isolated from marine sponge Monanchora pulchra by us. Here, anticancer activity and mechanism of action was investigated for the first time using a human prostate cancer (PCa) model. MomC was active in all PCa cell lines at low micromolar concentrations and induced an unusual caspase-independent, non-apoptotic cell death. Kinase activity screening identified activation of mitogen-activated protein kinase (MAPK) c-Jun N-terminal protein kinase (JNK1/2) to be one of the primary molecular mechanism of MomC anticancer activity. Functional assays demonstrated a specific and selective JNK1/2 activation prior to the induction of other cell death related processes. Inhibition of JNK1/2 by pretreatment with the JNK-inhibitor SP600125 antagonized cytotoxic activity of the marine compound. MomC caused an upregulation of cytotoxic ROS. However, in contrast to other ROS-inducing agents, co-treatment with PARP-inhibitor olaparib revealed antagonistic effects indicating an active PARP to be necessary for MomC activity. Interestingly, although no direct regulation of p38 and ERK1/2 were detected, active p38 kinase was required for MomC efficacy, while the inhibition of ERK1/2 increased its cytotoxicity. In conclusion, MomC shows promising activity against PCa, which is exerted via JNK1/2 activation and non-apoptotic cell death.

Identification of Fromiamycalin and Halaminol A from Australian Marine Sponge Extracts with Anthelmintic Activity against Haemonchus contortus.

There is an urgent need to discover and develop new anthelmintics for the treatment of parasitic nematodes of veterinary importance to circumvent challenges linked to drug resistant parasites. Being one of the most diverse natural ecosystems, the marine environment represents a rich resource of novel chemical entities. This study investigated 2000 extracts from marine invertebrates, collected from Australian waters, for anthelmintic activity. Using a well-established in vitro bioassay, these extracts were screened for nematocidal activity against Haemonchus contortus — a socioeconomically important parasitic nematode of livestock animals. Extracts (designated Mu-1, Ha-1 and Ha-2) from two marine sponges (Monanchora unguiculata and Haliclona sp.) each significantly affected larvae of H. contortus. Individual extracts displayed a dose-dependent inhibition of both the motility of exsheathed third-stage larvae (xL3s) and the development of xL3s to fourth-stage larvae (L4s). Active fractions in each of the three extracts were identified using bioassay-guided fractionation. From the active fractions from Monanchora unguiculata, a known pentacyclic guanidine alkaloid, fromiamycalin (1), was purified. This alkaloid was shown to be a moderately potent inhibitor of L4 development (half-maximum inhibitory concentration (IC50) = 26.6 ± 0.74 µM) and L4 motility (IC50 = 39.4 ± 4.83 µM), although it had a relatively low potency at inhibiting of xL3 motility (IC50 ≥ 100 µM). Investigation of the active fractions from the two Haliclona collections led to identification of a mixture of amino alcohol lipids, and, subsequently, a known natural product halaminol A (5). Anthelmintic profiling showed that 5 had limited potency at inhibiting larval development and motility. These data indicate that fromiamycalin, other related pentacyclic guanidine alkaloids and/or halaminols could have potential as anthelmintics following future medicinal chemistry efforts.

Effect of Pentacyclic Guanidine Alkaloids from the Sponge Monanchora pulchra on Activity of α-Glycosidases from Marine Bacteria.

The effect of monanchomycalin B, monanhocicidin A, and normonanhocidin A isolated from the Northwest Pacific sample of the sponge Monanchora pulchra was investigated on the activity of α-galactosidase from the marine γ-proteobacterium Pseudoalteromonas sp. KMM 701 (α-PsGal), and α-N-acetylgalactosaminidase from the marine bacterium Arenibacter latericius KMM 426T (α-NaGa). All compounds are slow-binding irreversible inhibitors of α-PsGal, but have no effect on α-NaGa. A competitive inhibitor d-galactose protects α-PsGal against the inactivation. The inactivation rate (kinact) and equilibrium inhibition (Ki) constants of monanchomycalin B, monanchocidin A, and normonanchocidin A were 0.166 ± 0.029 min−1 and 7.70 ± 0.62 μM, 0.08 ± 0.003 min−1 and 15.08 ± 1.60 μM, 0.026 ± 0.000 min−1, and 4.15 ± 0.01 μM, respectively. The 2D-diagrams of α-PsGal complexes with the guanidine alkaloids were constructed with “vessel” and “anchor” parts of the compounds. Two alkaloid binding sites on the molecule of α-PsGal are shown. Carboxyl groups of the catalytic residues Asp451 and Asp516 of the α-PsGal active site interact with amino groups of “anchor” parts of the guanidine alkaloid molecules.

The Effect of Pentacyclic Guanidine Alkaloids from the Marine Sponge Monanchora pulchra Lambe, 1894 on the Activity of Natural β-1,3-D-glucanase from the Marine Fungus Chaetomium indicum Corda, 1840 and the Marine Bivalve Mollusk Spisula sachalinensis, Schrenck, 1861

The effect of pentacyclic guanidine alkaloids monanchomycalin B, monanchocidin A and normonanchocidin A isolated from the Far-Eastern marine sponge Monanchora pulchra was investigated towards the activity of exo-β-1,3-D-glucanase from the filamentous marine fungus Chaetomium indicum and endo-β-1,3-D-glucanase LIV from the marine bivalve mollusk Spisula sachalinensis. All compounds were shown to be slow irreversible inhibitors of exo-β-1,3-D-glucanase and significantly activated endo-β-1,3-Dglucanase. The equilibrium inhibition constants (Ki, μM) and the inactivation rate constants (kinact, min–1) were determined for each compound. The inhibitory capacities of alkaloids were shown to depend on the structure of the “anchor” part of the molecule of the compounds. Normonanchocidin A was the best inhibitor of exo-β-1,3-D-glucanase from fungi. A possible biological role of these compounds in the life of sponges and their microbial symbionts is discussed here.

Monanchoxymycalin C with anticancer properties, new analogue of crambescidin 800 from the marine sponge Monanchora pulchra

A new pentacyclic guanidine alkaloid, monanchoxymycalin C (1) was isolated from a new collection of marine sponge Monanchora pulchra along with the known monanchoxymycalin A (2). The structure of 1 was elucidated on the basis of spectroscopic data. Monanchoxymycalin C exhibits cytotoxic activity against human cancer HeLa cells at low micromolar concentrations, induces apoptosis-related death of malignant cells and inhibits cancer cell colony formation. In addition, synergistic and additive effects have been observed in combination with cisplatin.

Normonanchocidins G and H, New Pentacyclic Guanidine Alkaloids from the Far-Eastern Marine Sponge Monanchora pulchra

Two new pentacyclic guanidine alkaloids, normonanchocidins G (1) and H (2) containing an unusual ω-2-hydroxy fatty acid moiety were isolated from the Far-Eastern marine sponge Monanchora pulchra. The structures of 1 and 2 were determined by 1D- and 2D-NMR spectroscopic and mass spectrometric data interpretation. Compounds 1 and 2 exhibit potent cytotoxic activities against human leukemia THP-1, HL-60 cells, human cervical epithelioid carcinoma HeLa cells and also have high impact on ability of HeLa cells to migrate.

Pentacyclic Guanidine Alkaloids from Far Eastern Sponge Monanchora Ulchra – Inhibitors of O-Glycosyl Hydrolases of Marine Macro- and Micro-organisms

Pentacyclic Guanidine Alkaloids from Far Eastern Sponge Monanchora Ulchra – Inhibitors of O-Glycosyl Hydrolases of Marine Macro- and Micro-organisms

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.

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.

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.

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.

Monanchomycalins A and B, unusual guanidine alkaloids from the sponge Monanchora pulchra

New pentacyclic guanidine alkaloids, monanchomycalins A (1) and B (2) were isolated from the marine sponge, Monanchora pulchra and their structures elucidated using NMR, HRMALDI-TOF-MS, and HRESI MS, as well as by chemical transformations of 1. Compounds 1 and 2 exhibited potent cytotoxic activities against HL-60 human leukemia cells with IC50 values of 120 and 140nM, respectively.

Crambescidin 800, a pentacyclic guanidine alkaloid, protects a mouse hippocampal cell line against glutamate-induced oxidative stress

Oxidative stress is implicated in the pathogenesis of neuronal degenerative diseases. In our search for protective substances against glutamate-induced oxidative stress using mouse hippocampal cell line HT22, we have isolated crambescidin 800, a pentacyclic guanidine alkaloid, from the Indonesian marine sponge, Monanchora ungiculata. Crambescidin 800 (1) protected HT22 cells against glutamate-induced oxidative toxicity at 0.06 μM (EC50) concentration. Crambescidin 800 (1) also protected HT22 and neuroblastoma cells from the oxidative stress induced by a hypoxic condition or nitric oxide (NO). Crambescidin 800 (1) showed no effect on the depletion of intracellular glutathione (GSH) of HT22 cells induced by glutamate, and production of reactive oxygen species (ROS) and activation of mitogen-activated protein kinase (MAPK) were inhibited only by the high concentration (1 μM) of 1.

Crambescidin 826 and dehydrocrambine A: new polycyclic guanidine alkaloids from the marine sponge Monanchora sp. that inhibit HIV-1 fusion.

Two new polycyclic guanidine alkaloids, crambescidin 826 (1) and dehydrocrambine A (2), and the known compounds crambescidin 800 (3) and fromiamycalin (4) were isolated from the marine sponge Monanchora sp. The structures of 1 and 2 were elucidated by 2D NMR and mass spectrometry, and relative stereochemistry was established by analysis of coupling constants and ROESY spectra. The pentacyclic guanidine alkaloids 1, 3, and 4 inhibit HIV-1 envelope-mediated fusion in vitro with IC(50)'s of 1-3 microM, while compound 2, a tricyclic guanidine alkaloid, showed weaker inhibition, with an IC(50) of approximately 35 microM.

Total synthesis of crambescidin 359.

[structure: see text] Crambescidin 359 (4), which is the "vessel part" of the pentacyclic guanidine alkaloid ptilomycalin A (1), was synthesized for the first time based upon successive 1,3-dipolar cycloaddition reaction. This synthesis established the absolute stereochemistry of 4.

Ptilomycalin A, crambescidin 800 and related new highly cytotoxic guanidine alkaloids from the starfishes Fromia monilis and Celerina heffernani

Two novel pentacyclic guanidine alkaloids, celeromycalin 3 and fromiamycalin 4, have been isolated from the New Caledonian starfishes Celerina heffernani and Fromia monilis, respectively. Also found in Celerina heffernani are the known ptilomycalin A ( 1) and crambescidin 800 ( 2), which latter has been also isolated from Fromia monilis. The new compounds exhibited an high cytotoxic activity like the previous crambescidins. These complex pentacyclic guanidines are typical sponges metabolites and their occurence in starfishes is noteworthy. Fromia monilis also contained the less active component 5, made up from an hydroxyspermidine residue linked to a long chain ω-hydroxyacid.