Densazalin,a New Cytotoxic Diazatricyclic Alkaloid from the Marine Sponge Haliclona densaspicula

Densazalin, a polycyclic alkaloid, was isolated from the marine sponge Haliclona densaspicula collected in Korea. The complete structure of the compound was determined by spectroscopic methods, including 1D and 2D nuclear magnetic resonance techniques, high-resolution mass spectrometry, and comparison of the calculated and measured electronic circular dichroism spectra. Densazalin possesses a unique 5,11-diazatricyclo[7.3.1.0^2,7]tridecan-2,4,6-triene moiety, which is connected by two linear carbon chains. This compound was derived from the biogenetic precursor bis-1,3-dialkylpyridnium. Densazalin exhibited cytotoxic activity on two human tumor cell lines (AGS and HepG2) in the Cell Counting Kit-8 (CCK-8) bioassay, with IC₅₀ values ranging from 15.5 to 18.4 μM.     

The Active Centres of Agelastatin A,a Strongly Cytotoxic Alkaloid of the Coral Sea Axinellid Sponge Agelas dendromorpha,as Determined by Comparative Bioassays with Semisynthetic Derivatives

Agelastatin A ( 1 ), an unusual alkaloid of the axinellid sponge Agelas dendromorpha from the Coral Sea, can be selectively acetylated (→ 7 ) or methylated at OH? C(8a) (→ 4 ), peracetylated (→ 8 ) or permethylated at OH? C(8a), NH(5), and NH(6) (→ 5 ), or, finally, subjected to C(9)? C(8a) (→ 14 ) or C(5b)? C(8a) β-elimination (→ 11–13 ), in a regiospecific manner or not, depending on the reaction conditions. Under acidic conditions, compound 12 adds H₂O or MeOH, regioselectively though not endo/exo stereoselectively, giving transoid/cisoid mixtures 1/18 or 4/19 , respectively. Similarly 11 or 13 add MeOH to give mixtures (?)- 2/20 or 15/16 , respectively. Compound 13 also adds AcOH giving mixture 8/17 . The intermediate cisoid form obtained on treatment of 21 with H₃O⁺ undergoes N(5)? N(6) bridging affording pentacyclic 22 which constitutes a proof for the cisoid configuration. From conformational studies, rules are devised that allow assigning the configuration of these compounds from NMR data. In vitro comparative cytotoxicity assays of these compounds show that for high cytotoxic activity, such as of 1 in vivo, unsubstituted OH? C(8a), H? N(5), H? N(6) moieties are needed in the natural B/D transoid configuration.     

Misenine,a Novel Macrocyclic Alkaloid with an Unusual Skeleton from the Mediterranean Sponge Reniera sp

PolycycJic marine alkaloids containing 3-alkylpyridine or partially reduced 3-alkylpyridine as basic building blocks represent an emerging and intriguing group of bioactive natural products from marine sponges. Since halitoxin,² the first example of this kind of alkaloid, was reported in 1978, many related alkaloids have been discovered from sponges of the order Haplosclerida. All of these alkaloids, in spite of formally exhibiting quite different frameworks, could biogeneticaliy derive from bis-3-alkylpyridine or reduced bis-3-alkylpyridine units. In the last decade, the knowledge of this fascinating group of compounds has increased remarkably. A recent review has exhaustively studied occurrence, distribution, plausible biogenetic origin and relatedness, as well as biological activities, of 3-alkylpyridine derived marine alkaloids.³     

Leucascandrolide B,a New 16-Membered,Extensively Methyl-Branched Polyoxygenated Macrolide from the Calcareous Sponge Leucascandra caveolata from Northeastern Waters of New Caledonia

We report a novel, extensively methyl-branched and polyoxygenated 16-membered macrolide, leucascandrolide B (=(1R*,5S*,7R*,9S*,13R*,14R*,15R*,11Z)-5-[(E)-1,4-dimethylhept-5-enyl]-1,7,9-trihydroxy-11,14-dimethyl-3-oxo-4,17-dioxabicyclo[11.3.1]heptadec-11-en-15-yl] carbamate; 2 ), isolated from the calcareous sponge Leucascandra caveolata Borojevic and Klautau from the northeastern coast of New Caledonia. The NMR structural assignments were corroborated by semisynthetic derivatives of 2 , the functional groups and atom connectivity by derivatives 4 – 6 (obtained by acetylation, oxidation, and elimination-solvation, resp.), and the relative configurations by derivative 7 (obtained by carbonation). The preferred conformation of 2 , centered on a chair-like tetrahydro-2H-pyran ring formed by intramolecular acetalization, was derived from molecular mechanics and semiempirical calculations which were in agreement with all NMR data. A dilactone `dimeric' structure 3 , indistinguishable from 2 on the basis of all above data, was ruled out by tandem MS-MS experiments.     

Streptomycindole,an Indole Alkaloid from a Marine Streptomyces sp. DA22 Associated with South China Sea Sponge Craniella australiensis

A new indole alkaloid, streptomycindole ( 1 ), and a known related compound, N‐phenylacetyl‐L ‐tryptophan ( 2 ), have been isolated from Streptomyces sp. DA22, associated with South China Sea sponge Craniella australiensis. Their structures were established on the basis of a combination of mass spectrometry, ¹H‐ and ¹³C‐NMR spectroscopic analyses, and chemical methods.     

Verapliquinones: Novel Diprenylquinones from an Aplidium sp. (Ascidiacea) of Ile-Verte Waters,Brittany

An Aplidium sp. (Ascidiacea), collected in French Atlantic waters near the Ile Verte, is shown to contain verapliquinone B ( 2 ) and verapliquinone D ( 6 ) as the first examples of linear diprenylquinones of the neryl type, besides their respective isomers 1 and 5 of the geranyl type.     

Conformational Preferences and Absolute Configuration of Agelastatin A,a Cytotoxic Alkaloid of the Axinellid Sponge Agelas dendromorpha from the Coral Sea,via combined molecular modelling,NMR, and exciton splitting for diamide and hydroxyamide derivatives

The absolute configuration of agelastatin A ( 1 ), the major, strongly cytotoxic alkaloid of the axinellid sponge Agelas dendromorpha from the Coral Sea, is proposed here to be (5aS,5bS,8aS,9aR), as deduced from combined molecular-mechanics calculations and a novel application of exciton splitting to the bis[4-(dimethylamino)benzoyl] compounds (–)- 9 and (–)- 13 , derivatives of a diamide and a hydroxyamide, respectively. The position of the conformational equilibrium of A 1 could be finely tuned by slight molecular changes. The minor analogue, agelastatin B ( 3 ), was isolated as the trimethyl derivative (–)- 4 .     

Dysideasterols A–E,Five New Uncommon Polyhydroxylated Steroids from the South China Sea Sponge Dysidea sp.

Five new uncommon polyhydroxylated steroids, dysideasterols A–E ( 1 – 5 ), were isolated from the South China Sea sponge Dysidea sp. Their structures were established by detailed analysis of spectral data and verified via single‐crystal X‐ray‐diffraction analysis of compound 1 . The absolute configuration of 1 was determined by the modified Mosher method.     

Novel Naamidine-Type Alkaloids and Mixed-Ligand Zinc(II) Complexes from a Calcareous Sponge,Leucetta sp., of the Coral Sea

As compounds from a calcareous sponge, Leucetta sp., of the Coral Sea, we isolated a series of novel naamidine-type alkaloids, 6 – 10 , which are oxidized at a single benzylic position. We also report on the first marine, mixed-ligand metal complex 5 and on the first natural metal complexes 3 and 4 derived from classical naamidines, i.e., 1 and 2 . The latter are also present in free form in the sponge.     

A New Tetracyclic Bromopyrrole-Imidazole Derivative through Direct Chemical Diversification of Substances Present in Natural Product Extract from Marine Sponge Petrosia (Strongylophora) sp.

Chemical diversification of substances present in natural product extracts can lead to a number of natural product-like compounds with a better chance of desirable bioactivities. The aim of this work was to discover unprecedented chemical conversion and produce new compounds through a one-step reaction of substances present in the extracts of marine sponges. In this report, a new unnatural tetracyclic bromopyrrole-imidazole derivative, rac-6-OEt-cylindradine A (1), was created from a chemically diversified extract of the sponge Petrosia (Strongylophora) sp. We also confirmed that 1 originated from naturally occurring (-)-cylindradine A (2) via a new reaction pattern. Moreover, (-)-dibromophakellin (3) and 4,5-dibromopyrrole-2-carboxylic acid (4), as well as 2, were reported herein for the first time in this genus. Studies on the possible reaction mechanism and bioactivities were also conducted. The results indicate that the direct chemical diversification of substances present in natural product extracts can be a speedy and useful strategy for the discovery of new compounds.     

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A,a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis

A dysregulation of the cell-death mechanism contributes to poor prognosis in lung cancer. New potent chemotherapeutic agents targeting apoptosis-deregulating molecules have been discovered. In this study, 22-(4-pyridinecarbonyl) jorunnamycin A (22-(4′py)-JA), a synthetic derivative of bistetrahydroisoquinolinequinone from the Thai blue sponge, was semisynthesized by the Steglich esterification method, and its pharmacological mechanism in non-small-cell lung cancer (NSCLC) was elucidated by a network pharmacology approach. All predicted targets of 22-(4′py)-JA and genes related to NSCLC were retrieved from drug-target and gene databases. A total of 78 core targets were identified, and their associations were analyzed by STRING and Cytoscape. Gene ontology and KEGG pathway enrichment analyses revealed that molecules in mitogen-activated protein kinase (MAPK) signaling were potential targets of 22-(4′py)-JA in the induction of NSCLC apoptosis. In silico molecular docking analysis displayed a possible interaction of ERK1/2 and MEK1 with 22-(4′py)-JA. In vitro anticancer activity showed that 22-(4′py)-JA has strong cytotoxic and apoptosis-inducing effects in H460, H292 and A549 NSCLC cells. Furthermore, immunoblotting confirmed that 22-(4′py)-JA induced apoptotic cell death in an ERK/MEK/Bcl-2-dependent manner. The present study demonstrated that 22-(4′py)-JA exhibited a potent anticancer effect that could be further developed for clinical application and showed that network pharmacology approaches are a powerful tool to illustrate the molecular pathways of new drugs or compounds.     

Soyauxinine,a New Indolopyridoquinazoline Alkaloid from the Stem Bark of Araliopsis soyauxii Engl. (Rutaceae)

The chemical investigation of the total alkaloid extract (TAE) of the stem bark of Araliopsis soyauxii (Rutaceae) afforded an unreported indolopyridoquinazoline (compound 1) along with nine previously known alkaloids 2–10. In addition, six semi-synthetic derivatives 3a–c, 4b, 5a and 6a were prepared by allylation and acetonidation of soyauxinium nitrate (5), edulinine (3), ribalinine (4) and arborinine (6). The structures and spectroscopic data of five of them are reported herein for the first time. The suggested mechanism for the formation of the new N-allylindolopyridoquinazoline 5a is presented. The structures of natural and derived compounds were determined employing extensive NMR and MS techniques. The absolute configuration of stereogenic centers in compounds 2–4 were determined using NOESY technique and confirmed by the single-crystal X-ray diffraction (SC-XRD) technique. The use of SC-XRD further enabled us to carry out a structural revision of soyauxinium chloride recently isolated from the same plant to soyauxinium nitrate (5). The TAE, fractions, compounds 1–7 and 9, and semi-synthetic derivatives 3a–c, 4b, 5a and 6a were evaluated for their cytotoxic activity towards the cervix carcinoma cell line KB-3-1. No significant activity was recorded for most of the compounds except for 9, which showed moderate activity against the tested cancer cell lines.     

Tambouranolide, a new cytotoxic hydroxybutanolide from a Tambourissa sp. (Monimiaceae)

A new cytotoxic hydroxybutanolide, tambouranolide, has been isolated by solid phase extraction from an ethanol extract of the dried roots of a species of Tambourissa (Monimiaceae) from the Madagascar rainforest. The structure was elucidated through the interpretation of spectral data and its comparison to data reported in the literature for related molecules. The compound showed moderate in vitro cytotoxicity with an IC50 of 8 micro g mL(-1) in the A2780 human ovarian cancer cell line assay.     

Synthesis,Crystal Structure and Catalytic Properties of a New 2D Nickel(II) Coordination Polymer Based on Flexible Bis(benzimidazole)

A new Ni(II) coordination polymer [Ni(L)2(SCN)2]n(L = 1,4-bis(benzimidazol-1-yl)butane) was synthesized hydrothermally and characterized by elemental analysis, IR spectroscopy and single-crystal X-ray diffraction. The title compound crystallizes in the monoclinic system, space group C2/c with a = 9.4760(3), b = 24.0408(8), c = 16.5871(5) A, β = 99.832(3)°, V = 3723.2(2) A3, Z = 4, Dc = 1.348 g/cm3, F(000) = 1576, the final R = 0.0486 and w R = 0.0936 for 2938 observed reflections with I 2σ(I) for the complex. Structural analysis shows that the coordination polymer possesses a 2D(4,4) layer structure which is composed of Ni(II) centers bridged by L ligand with two kinds of conformations and further assembled into a 3D supramolecular network via π-π stacking interactions. In addition, the fluorescence and catalytic properties, for the degradation of Congo red, of the complex were investigated.     

Synthesis, Crystal Structure and Cytotoxic Activity of a Novel Nickel(II) Complex with Schiff Base Derived from Salicylhydrazide

A novel Schiff base complex with π-conjugated system, [Ni(L1)2(py)2] 1 (L1 = (E)-N'-(2,4-dichlorobenzylidene)-2-oxidobenzohydraizide), was synthesized and characterized by elemental analysis and single-crystal X-ray determination. Complex 1 crystallizes in the monoclinic system, space group P21/n with a = 12.8286(10), b = 16.3573(13), c = 19.0206(14) , β = 108.2920(10)o, V = 3789.6(5) 3, Z = 4, Mr = 833.17, Dc = 1.460 g/cm3, μ = 0.843 mm-1, F(000) = 1704, the final R = 0.0537 and wR = 0.0640 for 3836 observed reflections with I > 2σ(I). In the molecular structure of 1, the NiII atoms are six-coordinated by two N and two O atoms from two Schiff base ligands (L1) and two N atoms from two pyridine solvent molecules to form a distorted octahedral geometry. The cytotoxic activities of complex 1 have been experimentally studied against a human HeLa cell in vitro.