Stereochemical evaluation of sesquiterpene quinones from two sponges of the genus Dactylospongia and the implication for enantioselective processes in marine terpene biosynthesis

Silver nitrate flash chromatography of the organic extract from the sponge Dactylospongia elegans has led to the isolation of three new sesquiterpene quinones isohyatellaquinone (7), 7,8-dehydrocyclospongiaquinone-2 (8) and 9-epi-7,8-dehydrocyclospongiaquinone-2 (9) together with the known quinones dictyoceratidaquinone (6), mamanuthaquinone (10), ilimaquinone (11), hyatellaquinone (12) and the sesterterpene furospinosulin (22). The relative stereochemistry of dictyoceratidaquinone (6) is assigned on the basis of NOESY analysis. A second species of Dactylospongia, thought to be new to science, was found to contain ent-(7) together with the new quinone neomamanuthaquinone (13). The isolation of antipodal sesquiterpenes from closely related species has implications for the stereochemical evaluation of terpene metabolites. The biosynthetic processes in these marine sponges may involve terpene synthases that do not discriminate chiral substrates or may result from the presence of multiple terpene synthases, each with differing enantioselectivity.     

Fascioquinols A-F: bioactive meroterpenes from a deep-water southern Australian marine sponge, Fasciospongia sp.

Chemical investigation of a southern Australian deep-water marine sponge, Fasciospongia sp., returned the new meroterpene sulfate fascioquinol A (1) together with a series of acid mediated hydrolysis/cyclization products, fascioquinols B (2), C (3) and D (4), and strongylophorine-22 (5). Additional co-metabolites include the new meroterpenes fascioquinol E (6) and fascioquinol F (8), together with the known sponge metabolite geranylgeranyl 1,4-hydroquinone (7). Structures were assigned to 1-8 on the basis of detailed spectroscopic analysis, chemical interconversion, mechanistic and biosynthetic considerations, and literature comparisons. The known 1,4-hydroquinone 7 was identified as the dominant cytotoxic principle in the Fasciospongia sp. extract, with selective inhibitory activity against gastric adenocarcinoma (AGS, IC₅₀ 8 μM) and neuroblastoma (SH-SY5Y, IC₅₀ 4 μM) cell lines. By contrast, while the fascioquinols displayed little or no inhibitory activity towards human cell lines, 1 and 2 displayed promising Gram-positive selective antibacterial activity towards Staphylococcus aureus (IC₅₀ 0.9-2.5 μM) and Bacillus subtilis (IC₅₀ 0.3-7.0 μM).     

Novel alkaloids, paxdaphnines A and B with unprecedented skeletons from the seeds of Daphniphyllum paxianum

Two novel Daphniphyllum alkaloids with unprecedented skeletons, namely paxdaphnines A (1) and B (2), have been isolated from the seeds of Daphniphyllum paxianum. Paxdaphnine A (1) is a 19-nor-Daphniphyllum alkaloid with highly caged skeleton, and paxdaphnine B (2) is the first 1,19-bisnor-Daphniphyllum alkaloid. The relative structures of 1 and 2 were elucidated by spectral methods, and their unique biosynthetic pathway postulated. The absolute structure of 1 was determined by X-ray diffraction of the iodide derivative (1a) of 1, and the absolute stereochemistry of 2 was proposed by correlation with the biosynthetic pathway for 1.     

Naupliolide, a sesquiterpene lactone with a novel tetracyclic skeleton from Nauplius graveolens subsp. odorus

The aerial parts of Nauplius graveolens subsp. odorus (Schousb) Wikl. afforded a novel sesquiterpene lactone (1) named naupliolide together with the known 6,7,9,10-tetradehydroasteriscanolide 2 and asteriscunolides A-D 3a-d. The structure of compound 1 corresponds to a novel skeleton of 14,15-dimethyl-7,13-dioxotricyclic[6.4.0.0^9,11]dodeca-12,13-olide, and was established on the basis of spectroscopic methods including 2D-NMR. The coexistence of naupliolide 1 together with the structurally related sesquiterpene lactones asterisculolides A-D (3a-d) and 6,7,9,10-tetradehydroasteriscanolide 2, seems to indicate their biosynthetic relationship.     

Agelasines O-U, new diterpene alkaloids with a 9-N-methyladenine unit from a marine sponge Agelas sp.

New diterpene alkaloids, agelasines O-U (1-7), have been isolated from an Okinawan marine sponge Agelas sp. The gloss structures and relative stereochemistries of 1-7 were elucidated from the spectroscopic data. Agelasines O-R (1-4) were the third examples of diterpene alkaloid with a 9-N-methyladenine and a pyrrole units. Agelasine O (1) has a halimane skeleton, while agelasines P-R (2-4) have a clerodane skeleton. Agelasines S-U (5-7) were new diterpene alkaloids with a 9-N-methyladenine unit consisting of a halimane skeleton, a labdane skeleton, and a clerodane skeleton, respectively. Agelasines O-R (1-4) and T (6) showed antimicrobial activities against several bacteria and fungi.     

Withaphysanolide A, a novel C-27 norwithanolide skeleton, and other cytotoxic compounds from Physalis divericata

A novel C-27 norwithasteroid, withaphysanolide A (1) containing a pyran ring was isolated from the aerial parts of Physalis divericata. Four known withaphysalins (2-5) and five physalins (6-10) were also isolated. The structural assignment for 1 was done based on spectroscopic and single-crystal X-ray diffraction data. Logical biosynthetic pathways were postulated. Compounds 6, 7, and 10 displayed potent cytotoxic activity against HCT-116 and H460 human cancer cell lines, with IC₅₀ values less than 2.0 μM.     

Isolation and synthesis of N-acyladenine and adenosine alkaloids from a southern Australian marine sponge, Phoriospongia sp.

Chemical fractionation of the southern Australian marine sponge Phoriospongia sp. (CMB-03107) yielded phorioadenine A (1) as a nematocidal agent and the first reported example of a 6-N-acyladenine natural product. The structure of 1 was confirmed by spectroscopic analysis and the chemical synthesis of racemic (1a) and enantiomeric (1b) analogues. HPLC–ESIMS analysis of the crude sponge extract with comparisons to the synthetic 6-N-acyladenosine 2a provided evidence that the biosynthetically related adenosine, phorioadenosine A (2), was present as a trace co-metabolite. The rare starfish metabolite asterubine (3) was also isolated as a co-metabolite, and its structure confirmed by spectroscopic analysis and chemical synthesis. Biological investigations confirmed that natural products 1–3 and synthetic analogues 1a–e and 2a were not cytotoxic to multiple mammalian cancer cell lines, or Gram-positive or -negative bacteria. Nematocidal activity (inhibition of larval development of Haemonchus contortus) detected in the Phoriospongia sp. extract was attributed to 1 (LD₉₉ 31 μg/mL), with preliminary structure–activity relationship investigations confirming the importance of the N-acyl side chain.     

New phlegmarane-type, cernuane-type, and quinolizidine alkaloids from two species of Lycopodium

Two new phlegmarane-type alkaloids, cermizines A (1) and B (2), three new quinolizidine alkaloids, cermizine C (3) and senepodines G (4) and H (5), and a new C₁₆N₂ type alkaloid consisting of a quinolizidine and a piperidine ring, cermizine D (6), as well as two new cernuane-type alkaloids, cernuine N-oxide (7) and lycocernuine N-oxide (8), have been isolated together with cernuine (9) and lycocernuine (10) from the club moss Lycopodium cernuum and L. chinense. The relative stereochemistry of 1-4 and 6, and the absolute stereochemistry of 5, 7, and 8 were elucidated by combination of NOESY correlations, modified Mosher's method, chemical transformations, and computational methods. Cermizine D (6) might be a biosynthetic intermediate of cernuane-type alkaloids such as 7-10.     

Convenient synthesis of a marine cyclopentanoid: untenone A

(±)-Untenone A, one of the marine cyclopentanoids, has been conveniently synthesized via (±)-cis-1-hexadecylcyclopent-2-en-1,4-diol 9 which has been produced from 1-hexadecylcyclopenta-1,3-diene 6 via photo-oxidation and the following reduction. The key step of the present synthesis is the selective alkylation of cyclopenta-1,3-diene to form 6. Optically active (−)- and (+)-untenone A have been prepared from (−)- and (+)-9, respectively, after enzymatic kinetic resolution of (±)-9.     

Spironaamidine, a new spiroquinone-containing alkaloid from the marine sponge Leucetta microraphis

Spironaamidine (1), a unique spiroquinone-containing alkaloid, was isolated from the marine sponge, Leucetta microraphis, along with two known imidazole alkaloids, naamidine H (2) and (9E)-clathridine 9-N-(2-sulfoethyl)imine (3). Spironaamidine (1) showed antimicrobial activity against Bacillus cereus.     

Structural and stereochemical investigations into bromotyrosine-derived metabolites from southern Australian marine sponges, Pseudoceratina spp.

Chemical investigation of a southern Australian sponge, Pseudoceratina sp., resulted in the isolation of twelve bromotyrosine-derived alkaloids, comprising four new metabolites, aplysamine-7 (1), (−)-purealin B (2), purealin C (3) and purealin D (4); two new spiroisoxazole enantiomers, (−)-purealidin R (5) and (−)-aerophobin-2 (6); five known metabolites (−)-pseudoceratinine A (7), (−)-aeroplysinin-1 (8), aplysamine-2 (9), purpuramine G (10) and purpuramine J (11); and an artifact 12 derived from ethanolysis of 5. Structures for 1-12 were assigned on the basis of detailed spectroscopic analysis. A second southern Australian Pseudoceratina sp. afforded the first recorded account of a racemic bromotyrosine-derived spiroisoxazole, (±)-purealin (13b), together with the known achiral precursor purealidin A (15). A literature review of marine bromotyrosine-derived spiroisoxazoles reaffirmed the published dominance of (+)-spiroisoxazoles, acknowledging several accounts of (−)-spiroisoxazoles, while also revealing a wide range of chiroptical measurements suggestive of variable optical purity. The Pseudoceratina sp. metabolites 1-12, 13b and 15 were assessed for antibiotic properties, with the new metabolites 3 and 13b exhibiting broad spectrum activity against several Gram-positive bacteria.     

Advanced precursors in marine biosynthetic study. Part 3: The biosynthesis of dichloroimines in the tropical marine sponge Stylotella aurantium

The biosynthetic origins of the dichloroimine group in the stylotellanes A and B 1, 2 have been investigated by incorporation of [¹⁴C]-labeled farnesyl isocyanide 7 and farnesyl isothiocyanate 3 into the sponge Stylotella aurantium.     

Total synthesis of eurypamides, marine cyclic-isodityrosines from the Palauan sponge Microciona eurypa

Total synthesis of eurypamides A, B, and D, 1, 2, and 4, has been successfully accomplished. The Tl(NO₃)₃ (TTN) oxidation of the halogenated bisphenols, 14a, 14b, 24, and 43, effected regio-controlled cyclization to provide the corresponding diaryl ethers, 15a, 15b, 25, and 46. This investigation revealed a structural revision of eurypamide A as to possess (2″S,3″R,4″S)-configuration (47), along with the spectral data of pure 2 and 4, which were previously characterized in a mixture.     

Structures and cytotoxicities of fascaplysin and related alkaloids from two marine phyla—Fascaplysinopsis sponges and Didemnum tunicates

The structural variations and bioactivity properties of the alkaloids in the fascaplysin (1) and the reticulatine (3) families were examined. Four organisms were analyzed consisting of two collections of the sponge Fascaplysinopsis reticulata and two collections of the tunicate Didemnum sp. Reported are the isolation of three new compounds: 3-bromofascaplysin (2), 14-bromoreticulatine (4), and 14-bromoreticulatate (6) along with reticulatate (5) previously known as a semi-synthetic product of 1. Compounds 1 and 5 showed selectivity in a cell based cytotoxicity assay.     

The first sorbicillinoid alkaloids, the antileukemic sorbicillactones A and B, from a sponge-derived Penicillium chrysogenum strain

The saltwater culture of a Penicillium chrysogenum strain isolated from the Mediterranean sponge Ircinia fasciculata yielded three new sorbicillin-derived compounds (1-3), whose structures were elucidated mainly by 2D NMR and mass spectrometry. Among them, sorbicillactones A (1) and B (2) are the first sorbicillinoid natural products that contain nitrogen. Compound 1 is anti-HIV active and it exhibits a strong cytotoxic activity against L5178y leukemic cells, combined with a relatively low toxicity to cervical carcinoma HeLa S3 cells and pheochromocytoma PC 12 cells. The absolute configurations of 1 and 2 were elucidated by quantum chemical calculation of circular dichroism (CD) spectra. Another compound isolated, sorbivinetone (3), might be an artifact derived from sorbicillinol (4) by Diels-Alder reaction with ethyl vinyl ether. Furthermore, the known sorbicillinoid fungal metabolites oxosorbicillinol (5), sorbicillin (6), and bisvertinolone (7) were identified, as well as the alkaloids meleagrine and roquefortine C. The biosynthetic origin of sorbicillactone A (1) from acetate, alanine, and methionine was investigated by feeding experiments with ¹³C-labeled precursors.     

Aplyronine A, a potent antitumor macrolide of marine origin, and the congeners aplyronines B and C: isolation, structures, and bioactivities

Aplyronine A (2), a potent antitumor macrolide was isolated from the sea hare Aplysia kurodai together with the congeners aplyronines B (3) and C (4). The absolute stereostructure of aplyronine A (2) was determined by the instrumental analysis (mainly NMR and MS) and the enantioselective synthesis of the fragments obtained from chemical degradation of aplyronine A (2). The structures of aplyronines B (3) and C (4) were also elucidated. Cytotoxicity and antitumor activity of aplyronine A (2) were evaluated.     

Combined biotransformations of 4(20),11-taxadienes

Taxuyunnanine C (1) and its analogs (2 and 3), the C-14 oxygenated 4(20), 11-taxadienes from callus cultures of Taxus sp., were regio- and stereo-selectively hydroxylated at the 7β position by a fungus, Abisidia coerulea IFO 4011, and it was interesting that the longer the alkyl chain of the acyloxyl group at C-14 became, the higher the yield of 7β-hydroxylated product was. Besides the three 7β-hydroxylated products (5, 9, 17), other nine new products (7, 11, 12, 14, 15, 16, 18, 20 and 21) and six known products (4, 6, 8, 10, 13 and 19) were obtained. Subsequently, the acetylated derivatives (24 and 27) of 7β-and 9α-hydroxylated products of 1 were regio- and stereo-specifically hydroxylated at the 9α position by Ginkgo cells and 7β position by A. coerulea, respectively. Thus, the two specific oxidations have been combined. These bioconversions would provide not only valuable intermediates for the semi-synthesis of paclitaxel or other bioactive taxoids from 1 and its analogs, but also some useful hints for the biosynthetic pathway of taxoid in the natural Taxus plant.     

Further studies on the constituents of the gorgonian octocoral Pseudopterogorgia elisabethae collected in San Andrés and Providencia islands, Colombian Caribbean: isolation of a putative biosynthetic intermediate leading to erogorgiaene

Chemical investigations of the MeOH-CH₂Cl₂ extract of Pseudopterogorgia elisabethae specimens collected in the islands of San Andrés and Providencia, Colombian Caribbean, yielded four new diterpenes (1, 3, 5, 7) along with seco-pseudopterosin J (8), and amphilectosins A (9) and B (10). The structures of the new compounds were established through spectral studies as an elisabethatriene analog named elisabethatrienol (1), 10-acetoxy-9-hydroxy- and 9-acetoxy-10-hydroxy-amphilecta-8,10,12,14-tetraenes (isolated as an interconverting mixture) (3), amphilecta-8(13),11,14-triene-9,10-dione (5), and a seco-pseudopterosin 7-O-α-l-fucopyranoside named seco-pseudopterosin K (7). Elisabethatrienol can be regarded as a biosynthetic intermediate leading to erogorgiaene.     

Dactylospongiaquinone, a new meroterpenoid from the Australian marine sponge Dactylospongia n. sp.

Chemical investigation of the sponge Dactylospongia n. sp. collected near Mooloolaba, S.E. Queensland, has led to the isolation of dactylospongiaquinone (7) together with the known quinones (2-5). The new metabolite 7 possesses a different carbon framework from the known dictyoceratidaquinone (9) and is suggested to possess a cis-fused ring junction by extensive NOESY studies combined with molecular modelling calculations. The relative stereochemistry of the previously described cyclospongiaquinone-1 (3) and dehydrocyclospongiaquinone-1 (4) is also assigned on the basis of NOESY analyses. Full NMR spectroscopic assignments are provided for all compounds.     

Enantioselective synthesis of aurisides A and B, cytotoxic macrolide glycosides of marine origin

The enantioselective synthesis of aurisides A and B, macrolide glycosides of marine origin, was achieved by a convergent approach. The C1-C9 segment 4 was prepared from (R)-pantolactone, and the C10-C17 segment 14 was synthesized from (R)-glycidyl trityl ether. The Nozaki-Hiyama-Kishi reaction between 4 and 14 and subsequent reactions gave seco acid 10, which was converted into the aglycon (3) of aurisides by construction of the 14-membered lactone and bromine-substituted conjugated diene. The glycosylation reaction of the aglycon provided aurisides A and B.