Total Synthesis and Biological Activity of Marine Alkaloid Eudistomins Y1–Y7 and Their Analogues

Eudistomin Y class compounds are a series of β-carbolines which was originally isolated from a marine turnicate or ascidian near the South Korea Sea. These compounds contain bromo-substituted groups, which is one of the typical characters of marine natural products. We report herein the chemical synthesis and biological evaluation of seven new β-carboline-based metabolites, Eudistomins Y₁–Y₇, and their hydroxyl-methylated phenyl derivatives. Using bromo-substituted tryptamines and bromo-substituted phenylglyoxals as the key intermediates, Eudistomins Y₁–Y₇ and their derivatives were synthesized via the acid-catalyzed Pictet-Spengler reaction and fully characterized by ¹H- and ¹³C-NMR and mass spectroscopy. Biological studies revealed that all of the compounds showed moderate growth inhibitory activity against breast carcinoma cell line MDA-231 with IC₅₀ of 15–63 μM and the inhibitory activities of hydroxyl-methylated phenyl products were higher than that of the corresponding natural products Eudistomins Y₁–Y₇.     

Synthesis of (3S,3′S)- and meso-Stereoisomers of Alloxanthin and Determination of Absolute Configuration of Alloxanthin Isolated from Aquatic Animals

In order to determine the absolute configuration of naturally occurring alloxanthin, a HPLC analytical method for three stereoisomers 1a–c was established by using a chiral column. Two authentic samples, (3S,3′S)- and meso-stereoisomers 1b and 1c, were chemically synthesized according to the method previously developed for (3R,3′R)-alloxanthin (1a). Application of this method to various alloxanthin specimens of aquatic animals demonstrated that those isolated from shellfishes, tunicates, and crucian carp are identical with (3R,3′R)-stereoisomer 1a, and unexpectedly those from lake shrimp, catfish, biwa goby, and biwa trout are mixtures of three stereoisomers of 1a–c.     

An Improved High Yield Total Synthesis and Cytotoxicity Study of the Marine Alkaloid Neoamphimedine: An ATP-Competitive Inhibitor of Topoisomerase IIα and Potent Anticancer Agent

Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (≤6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC₅₀ values) in all, with significant potency against colorectal cancer (lowest IC₅₀ = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis.     

Synthesis and properties of symmetrically substituted 4,4′-bis(1,3,5-triazinyl)-diamino stilbene-2,2′-disulfonic acid derivatives as UV absorbing and fluorescent whitening agents

The fluorescence properties of textiles dyed with optical brighteners have been widely reported in literature. However, little sufficient study has investigated the UV protection properties of textiles dyed with fluorescent whitening agents (FWAs). This study reports the synthesis of a series of stilbene-triazine compounds and their performance on cotton fiber as UV absorbing and FWAs. Triazinyldiaminostilbene compounds were synthesized by reacting 4,4′-diaminostilbene-2,2′-disulfonic acid with 2,4,6-trichloro-1,3,5-triazine to give 4,4′-bis(4,6-dichloro-1,3,5-triazin-2-yl)aminostilbene-2,2′-disulphonic acid. This intermediate was further condensed in two steps with amines by nucleophilic substituents on their triazine moiety. The structure of synthesized compounds were characterized by spectroscopic techniques i.e. IR, UV, elemental analysis and conformed by proton NMR Spectroscopy. These compounds were applied to cotton fiber as fluorescent whitening and UV absorbing agents. Their performances were evaluated with regards to whitening effects, ultraviolet protection factor (UPF), degree of exhaustion and fastness test.     

Synthesis of PPAR-γ Activators Inspired by the Marine Natural Product,Paecilocin A

A series of N-substituted phthalimide derivatives were synthesized based on a pharmacophore study of paecilocin A (a natural PPAR-γ agonist) and synthetic leads. The introduction of hydrophilic and hydrophobic groups to the phthalimide skeleton yielded compounds 3–14. Compound 7 showed significant PPAR-γ activation in a luciferase assay using rat liver Ac2F cells. Docking simulations showed that a free hydroxyl group on the phthalimide head and a suitable hydrophilic tail, including a phenyl linker, were beneficial for PPAR-γ activation. Compound 7 and rosiglitazone concentration-dependently activated PPAR-γ with EC₅₀ values of 0.67 μM and 0.028 μM, respectively. These phthalimide derivatives could be further investigated as a new class of PPAR-γ ligands.     

Synthesis and application of o,o′-dihydroxyazo dyes and their metal complexes

This paper presents the synthesis of metal complex acid dyes obtained from the reaction of o,o′-dihydroxyazo dyes and chromium and cobalt sulfate. The ¹H-NMR, FT-IR and UV/Visible Spectrophotometer, TLC (Thin Layer Chromatography) and ICP (Ion Chromatography) of the intermediates and the metal complexes were studied and compared. Their properties such as dyeing, fastness and toxicity on nylon were also assessed according to standard methods.     

Isolation and Total Synthesis of Stolonines A–C,Unique Taurine Amides from the Australian Marine Tunicate Cnemidocarpa stolonifera

Cnemidocarpa stolonifera is an underexplored marine tunicate that only occurs on the tropical to subtropical East Coast of Australia, with only two pyridoacridine compounds reported previously. Qualitative analysis of the lead-like enhanced fractions of C. stolonifera by LC-MS dual electrospray ionization coupled with PDA and ELSD detectors led to the identification of three new natural products, stolonines A–C (1–3), belonging to the taurine amide structure class. Structures of the new compounds were determined by NMR and MS analyses and later verified by total synthesis. This is the first time that the conjugates of taurine with 3-indoleglyoxylic acid, quinoline-2-carboxylic acid and β-carboline-3-carboxylic acid present in stolonines A–C (1–3), respectively, have been reported. An immunofluorescence assay on PC3 cells indicated that compounds 1 and 3 increased cell size, induced mitochondrial texture elongation, and caused apoptosis in PC3 cells.     

Report of the joint meeting of the Potato Section of EUCARPIA and the Section Breeding and varietal assessment of the EAPR, 3–7 July, 2000, Warsaw (Poland)

Report

Report of the joint meeting of the Potato Section of EUCARPIA and the Section Breeding and varietal assessment of the EAPR, 3–7 July, 2000, Warsaw (Poland)     

Marine Pharmacology in 2009–2011: Marine Compounds with Antibacterial,Antidiabetic, Antifungal,Anti-Inflammatory,Antiprotozoal, Antituberculosis,and Antiviral Activities; Affecting the Immune and Nervous Systems,and other Miscellaneous Mechanisms of Action ?

The peer-reviewed marine pharmacology literature from 2009 to 2011 is presented in this review, following the format used in the 1998–2008 reviews of this series. The pharmacology of structurally-characterized compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacological activities were reported for 102 marine natural products. Additionally, 60 marine compounds were observed to affect the immune and nervous system as well as possess antidiabetic and anti-inflammatory effects. Finally, 68 marine metabolites were shown to interact with a variety of receptors and molecular targets, and thus will probably contribute to multiple pharmacological classes upon further mechanism of action studies. Marine pharmacology during 2009–2011 remained a global enterprise, with researchers from 35 countries, and the United States, contributing to the preclinical pharmacology of 262 marine compounds which are part of the preclinical pharmaceutical pipeline. Continued pharmacological research with marine natural products will contribute to enhance the marine pharmaceutical clinical pipeline, which in 2013 consisted of 17 marine natural products, analogs or derivatives targeting a limited number of disease categories.     

Antibacterial Activity of 2-(2′,4′-Dibromophenoxy)-4,6-dibromophenol from Dysidea granulosa

2-(2′,4′-Dibromophenoxy)-4,6-dibromophenol isolated from the marine sponge Dysidea granulosa (Bergquist) collected off the coast of Lakshadweep islands, Indian Ocean, exhibited potent and broad spectrum in-vitro antibacterial activity, especially against methicillin resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA), vancomycin resistant Enterococci (VRE), vancomycin sensitive Enterococci (VSE) and Bacillus spp. Minimal inhibitory concentration (MIC) was evaluated against 57 clinical and standard strains of Gram positive and Gram negative bacteria. The observed MIC range was 0.117–2.5 μg/mL against all the Gram positive bacteria and 0.5–2 μg/mL against Gram negative bacteria. The in-vitro antibacterial activity observed was better than that of the standard antibiotic linezolid, a marketed anti-MRSA drug. The results establish 2-(2′,4′-dibromophenoxy)-4,6-dibromophenol, as a potential lead molecule for anti-MRSA and anti-VRE drug development.     

Marine Bromophenol Bis (2,3-Dibromo-4,5-dihydroxy-phenyl)-methane Inhibits the Proliferation,Migration, and Invasion of Hepatocellular Carcinoma Cells via Modulating β1-Integrin/FAK Signaling

Bis (2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a natural bromophenol compound derived from marine algae. Previous reports have shown that BDDPM possesses antimicrobial activity. In the present study, we found that BDDPM has cytotoxic activity on a wide range of tumor cells, including BEL-7402 cells (IC₅₀ = 8.7 μg/mL). Further studies have shown that prior to the onset of apoptosis, the BDDPM induces BEL-7402 cell detachment by decreasing the adherence of cells to the extracellular matrix (ECM). Detachment experiments have shown that the treatment of BEL-7402 cells with low concentrations of BDDPM (5.0 μg/mL) significantly inhibits cell adhesion to fibronectin and collagen IV as well as cell migration and invasion. High doses of BDDPM (10.0 μg/mL) completely inhibit the migration of BEL-7402 cells, and the expression level of MMPs (MMP-2 and MMP-9) is significantly decreased. Moreover, the expression of β1-integrin and focal adhesion kinase (FAK) is found to be down-regulated by BDDPM. This study suggests that BDDPM has a potential to be developed as a novel anticancer therapeutic agent due to its anti-metastatic activity and also indicates that BDDPM, which has a unique chemical structure, could serve as a lead compound for rational drug design and for future development of anticancer agents.     

Vitamin C and quercetin modulate DNA-damaging effect of N-methyl-N′-nitro-N-nitrosoguanidine (MNNG)

The effects of natural compounds, vitamin C and quercetin, present in fruitsand vegetables, on the DNA damaging activity of a food carcinogen N-methyl-N-nitro-N-nitrosoguanidine (MNNG) were examinedusing the comet assay. Vitamin C, at a concentration of 50 M,inhibited MNNG-induced DNA damage in human lymphocytes. Quercetin,up to a concentration of 10 M, increased the extent of DNA damage,but at concentrations above 10 M decreased damage below controlvalues. Furthermore, quercetin had a strong antioxidant activity againstoxidative damage evoked by H₂O₂ at 10 M. The resultsobtained suggest that vitamin C and quercetin may have anti- orpro-oxidative properties depending on the state of the cell.     

Effects of temperature and pH on the inhibition of Bensulfuron-Methyl(BSM)

Bensulfuron-Methyl(BSM) is a highly active sulfonylurea herbicide that effectively controls most annual and perennial broadleaf or sedge weeds in paddy field. However, the activity of BSM is affected by several evironmental factors. Using corn seedlings as material, we found that under different temperatures     

6″-Debromohamacanthin A,a Bis (Indole) Alkaloid,Inhibits Angiogenesis by Targeting the VEGFR2-Mediated PI3K/AKT/mTOR Signaling Pathways

Hamacanthins, bis (indole) alkaloids, are found in a few marine sponges, including Spongosorites sp. Hamacanthins have been shown to possess cytotoxic, antibacterial and antifungal activities. However, the precise mechanism for the biological activities of hamacanthins has not yet been elucidated. In the present study, the anti-angiogenic effects of 6″-debromohamacanthin A (DBHA), an active component of isolated hamacanthins, were evaluated in cultured human umbilical vascular endothelial cells (HUVEC) and endothelial-like cells differentiated from mouse embryonic stem (mES) cells. DBHA significantly inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration and tube formation in the HUVEC. DBHA also suppressed the capillary-like structure formation and the expression of platelet endothelial cell adhesion molecule (PECAM), an endothelial biomarker, in mES cell-derived endothelial-like cells. To further understand the precise molecular mechanism of action, VEGF-mediated signaling pathways were analyzed in HUVEC cells and mES cell-derived endothelial-like cells. DBHA suppressed the VEGF-induced expression of MAPKs (p38, ERK and SAPK/JNK) and the PI3K/AKT/mTOR signaling pathway. In addition, DBHA inhibited microvessel sprouting in mES/EB-derived embryoid bodies. In an ex vivo model, DBHA also suppressed the microvessel sprouting of mouse aortic rings. The findings suggest for the first time that DBHA inhibits angiogenesis by targeting the vascular endothelial growth factor receptor 2 (VEGFR2)-mediated PI3K/AKT/mTOR signaling pathway in endothelial cells.     

Butremycin,the 3-Hydroxyl Derivative of Ikarugamycin and a Protonated Aromatic Tautomer of 5′-Methylthioinosine from a Ghanaian Micromonospora sp. K310

A new actinomycete strain Micromonospora sp. K310 was isolated from Ghanaian mangrove river sediment. Spectroscopy-guided fractionation led to the isolation of two new compounds from the fermentation culture. One of the compounds is butremycin (2) which is the (3-hydroxyl) derivative of the known Streptomyces metabolite ikarugamycin (1) and the other compound is a protonated aromatic tautomer of 5′-methylthioinosine (MTI) (3). Both new compounds were characterized by 1D, 2D NMR and MS data. Butremycin (2) displayed weak antibacterial activity against Gram-positive S. aureus ATCC 25923, the Gram-negative E. coli ATCC 25922 and a panel of clinical isolates of methicillin-resistant S. aureus (MRSA) strains while 3 did not show any antibacterial activity against these microbes.     

Identification and Characterization of Two “Sensory Neuron Membrane Proteins” (SNMPs) of the Desert Locust,Schistocerca gregaria (Orthoptera: Acrididae)

Pheromone-responsive neurons of insects not only require specific receptors but in addition several auxiliary components, including the “sensory neuron membrane protein,” SNMP. Accordingly, SNMP is considered as a marker for neurons responding to pheromones. For the desert locust Schistocerca gregaria, it is known that the behavior, including aggregation behavior and courtship inhibition, is largely controlled by pheromones. However, little is known about pheromones, their receptors, and the pheromone-responsive cells in locusts. In this study, we have identified two SNMP subtypes, SNMP1 and SNMP2, and compared their phylogenetic relationship and primary structure motifs with SNMPs from other species. Both SNMPs were found in chemosensory tissues, especially the antennae. Employing double in situ hybridization, we identified and localized the SNMP-expressing cells in the antennae. Cells expressing SNMP1 were localized to sensilla trichodea but also to sensilla basiconica, which in locust respond to pheromones. One or a few cells express SNMP1 within the multineuron clusters from sensilla basiconica, whereas the SNMP2 subtype was expressed in cells surrounding the neuron clusters, possibly supporting cells. Based on the finding that SNMP1 is expressed in distinct neurons under chemosensory sensilla, it is conceivable that these cells may represent pheromone-responsive neurons of the desert locust.