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New bicyclic guanidine alkaloid, urupocidin C (Ur-C) along with the previously known urupocidin A (Ur-A) were isolated from the rare deep-sea marine sponge Monanchora pulchra, harvested in Northwestern Pacific waters. The unique structure of Ur-C was elucidated using 1D and 2D NMR spectroscopy as well as mass spectra. We discovered a promising selectivity of both alkaloids for human prostate cancer (PCa) cells, including highly drug-resistant lines, compared to non-malignant cells. In cancer cells, marine derived compounds were able to induce G1- and S-cell cycle arrest as well as caspase-mediated cell death. For the first time we have identified mitochondrial targeting as a central mechanism of anticancer action for these and similar molecules. Thus, treatment with the isolated alkaloids resulted in mitochondrial membrane permeabilization consequently leading to the release of cytotoxic mitochondrial proteins to cellular cytoplasm, ROS upregulation, consequent activation of caspase-9 and -3, followed by PARP cleavage, DNA fragmentation, and apoptosis. Moreover, synergistic effects were observed when Ur-A and Ur-C were combined with clinically approved PARP inhibitor olaparib. Finally, these alkaloids exhibited additive effects in combination with docetaxel and androgen receptor inhibitor enzalutamide, both applied in PCa therapy. In conclusion, urupocidin-like compounds are promising lead molecules for the development of new drugs for the treatment of advanced PCa.

The absolute configuration of the cytotoxic guanidine alkaloid monanchocidin A with 11 stereogenic centers from the marine sponge Monanchora pulchra was determined as 5 R, 8 S, 10 S, 13 R, 14 S, 15 R, 19 R, 23 R, 37 S, 42 S, 43 R after extensive reductive degradation and conversion of the resulting alcohols to MTPA derivatives.

The first representatives of a new group of manzamine-related alkaloids with a previously unknown skeletal systems, namely, lissodendoric acids A (1) and B (2), were isolated from the sponge Lissodendoryx florida collected from the Sea of Okhotsk. The structures and absolute configurations have been elucidated by extensive spectroscopic analysis together with chemical transformations and quantum-chemical modeling. The lissodendoric acids show a potent capability to decrease the production of reactive oxygen species in neuroblastoma Neuro 2a and somewhat increase the survival of these cells upon treatment with 6-hydroxydopamine (an in vitro antiparkinson biotest).

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.

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.

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.

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.

Urupocidins A and B (1 and 2), bisguanidine alkaloids with an unprecedented skeleton system, derived from polyketide precursors and containing an unusual N-alkyl-N-hydroxyguanidine moiety, have been isolated from the sponge Monanhora pulchra. The structures of 1 and 2, including absolute configuration, were established using the detailed analysis of 1D and 2D NMR, CD, and mass spectra as well as chemical transformations. Compound 1 increases nitric oxide production in murine macrophages via inducing iNOS expression.

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.

New unusual polycyclic guanidine alkaloids monanchocidins B-E (2-5) along with monanchocidin A (1), which we recently described, were isolated from the Far-Eastern marine sponge Monanchora pulchra. Their structures were established using spectroscopic data and chemical transformations. Compounds 1-5 show potent cytotoxic activities against HL-60 human leukemia cells with IC50 values of 540, 200, 110, 830, and 650 nM, respectively.

Three new aaptamine-type alkaloids, 2,3-dihydro-2,3-dioxoaaptamine (1), 6-(N-morpholinyl)-4,5-dihydro-5-oxo-demethyl(oxy)aaptamine (2) and 3-(methylamino)demethyl(oxy)aaptamine (3), along with known aaptamines were isolated from the sponge Aaptos sp. Their structures were determined on the basis of detailed analysis of their 1D and 2D NMR spectroscopic and mass spectral data. The isolated compounds induced apoptosis in human leukemia THP-1 cells.

A series of aaptamines, including one new alkaloid (1), were isolated from the marine sponge Aaptos sp. collected in Vietnamese waters. The structure of 1 was elucidated using NMR and HRESIMS, as well as by chemical transformation of 1 to the previously known aaptamine and established as 3-N-morpholinyl-9-demethyl(oxy)aaptamine. The isolated compounds showed a potential cancer preventive activity.

The anticancer effect of thiacarpine, a synthetic analogue of the known cytotoxic alkaloid polycarpine isolated from the Pacific ascidian Polycarpa aurata, was investigated in vivo in experiments using mouse solid Ehrlich carcinoma tumor as the target. A high-resolution magnetic resonance imaging (MRI) technique using a MR tomograph "PharmaScan" US70/16 (Bruker, Ettlingen, Germany) was used for visualization and quantification of tumor size. Fluorescence microscopy and image analysis were applied to determine Ehrlich carcinoma cell chromatin condensing (apoptosis) and necrosis in Ehrlich carcinoma cells at the action of thiacarpine in in vitro experiments. The scan and size calculations of the tumor and some mouse organs were carried out during the experiments. Thiacarpine in a total dose of 100 mg/kg was found to exhibit the delay in growth of the mouse tumor. The antineoplastic effect of this compound was accompanied by an increase in the lifetime of experimental mice in comparison with the control group of animals. Our data show that the ability of thiacarpine to induce apoptosis in carcinoma cells may contribute to thiacarpine anticancer effects against mice solid Ehrlich carcinoma in vivo detected by MRI.

Purpose: Polycarpine from ascidian Polycarpa aurata was previously found to be active against different human tumor cells. In this study, we investigated the antitumor mechanisms of polycarpine and its synthetic derivative, desmethoxyethoxy-polycarpine (dimethylpolycarpine), through the induction of apoptosis. This new knowledge regarding the proapoptotic action of polycarpine and dimethylpolycarpine should lead to a better understanding of their effects and development of a new class of anticancer drugs., Methods: Apoptosis was clearly observed by flow cytometry and Western blotting using an antibody against cleaved caspase-3 as an apoptotic marker., Results: Polycarpines differentially activated p38 kinase, JNKs, and ERKs in JB6 Cl 41 cells. The polycarpines-induced apoptosis was decreased in cells expressing a dominant-negative mutant of JNK. Both compounds stimulated p53-dependent transcriptional activity and phosphorylation. Induction of p53-phosphorylation at serine 15 was suppressed in JNKI and JNK2 knockout cells. Furthermore, polycarpines were unable to induce apoptosis in p53-deficient MEFs in contrast to a strong induction of apoptosis in wild type MEFs, suggesting that p53 is involved in apoptosis induced by polycarpines. The p53 phosphorylation in turn was mediated by activated JNKs., Conclusions: These results indicate that all three MAPK signaling pathways are involved in the response of JB6 cells to treatment with polycarpines. Evidence also supports a proapoptotic role of the JNKs signaling pathway in vivo and clearly indicates that JNKs are required for phosphorylation of c-Jun, activation of p53, and subsequent apoptosis induced by polycarpines.

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. [ABSTRACT FROM AUTHOR]

Nicotinic acetylcholine receptors (nAChRs) fulfill a variety of functions making identification and analysis of nAChR subtypes a challenging task. Traditional instruments for nAChR research are d-tubocurarine, snake venom protein α-bungarotoxin (α-Bgt), and α-conotoxins, neurotoxic peptides from Conus snails. Various new compounds of different structural classes also interacting with nAChRs have been recently identified. Among the low-molecular weight compounds are alkaloids pibocin, varacin and makaluvamines C and G. 6-Bromohypaphorine from the mollusk Hermissenda crassicornis does not bind to Torpedo nAChR but behaves as an agonist on human α7 nAChR. To get more selective α-conotoxins, computer modeling of their complexes with acetylcholine-binding proteins and distinct nAChRs was used. Several novel three-finger neurotoxins targeting nAChRs were described and α-Bgt inhibition of GABA-A receptors was discovered. Information on the mechanisms of nAChR interactions with the three-finger proteins of the Ly6 family was found. Snake venom phospholipases A2 were recently found to inhibit different nAChR subtypes. Blocking of nAChRs in Lymnaea stagnalis neurons was shown for venom C-type lectin-like proteins, appearing to be the largest molecules capable to interact with the receptor. A huge nAChR molecule sensible to conformational rearrangements accommodates diverse binding sites recognizable by structurally very different compounds. [ABSTRACT FROM AUTHOR]

Abstract: Two new unusual alkaloids were isolated from the sponge Penares sp., collected from Viet Nam waters (the South China Sea). The structures of these compounds were established by analysis of 1D, 2D NMR (1H–1H COSY, DEPT, HSQC, HMBC, H2BC, and NOE), and MS data. Compound 1 shows moderate cytotoxicity against the human tumor cells HL-60 and HeLa. [Copyright &y& Elsevier]

New ionic compounds containing an alkaloidal cation and a steroidal anion have been isolated by reverse-phase liquid chromatography from the extracts of the starfish Lethasterias nanimensis chelifera. Their structures have been elucidated by NMR and mass spectroscopy as 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolinium salts of 3-O-sulfoasterone 1, 3-O-sulfoisoasterone 2 and 3-O-sulfothornasterol A 3. In addition, the alkaloid 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCA) 4 was found in this starfish. [Copyright &y& Elsevier]