Aaptanone, a novel zwitterionic metabolite of the aaptamine class with an oxygenated 1,6-naphthyridine core from the Vietnamese marine sponge Aaptos aaptos

A new zwitterionic compound, aaptanone, having a rare oxygenated 1,6-naphthyridine core, has been isolated from the Vietnamese marine sponge Aaptos aaptos, along with the known metabolites, aaptamine, isoaaptamine, and their hydrochloride salts. The structure of aaptanone was determined as 8-methoxy-1-methyl-5,6-dioxo-5,6-dihydro-4H-benzo[de]-1,6-naphthyridine-1-ium-9-olate from spectroscopic data, X-ray analysis, and by spectroscopic analysis of an N-methyl derivative.     

Constituents of the Leaves and Stem Bark of Aglaia foveolata

The previously known potent cytotoxic agent silvestrol (1) (0.002% w/w yield) and five new flavagline derivatives (2-6) were isolated from the leaves of Aglaia foveolata collected in Indonesia. The new compound 5 has an unprecedented cyclic amide moiety in its cyclopenta[b]benzopyran skeleton, while compound 6 is a novel benzo[b]oxepine derivative in which the oxepine ring is cleaved. Pyramidatine (7), a biogenetic precursor of the new flavaglines 2-6, was isolated from the leaf extract investigated. Silvestrol was also isolated from the stem bark of A. foveolata (yield of 0.02% w/w) along with a new baccharane-type triterpenoid (8). The structures of the new compounds were elucidated on the basis of their NMR and mass spectrometric data. All new compounds isolated were tested against a panel of cancer cell lines, but only compound 2 was cytotoxic (IC₅₀ range=1.4-1.8 μM), and is the first member of the cyclopenta[b]benzopyran class found to exhibit this type of activity. Compound 2 also showed significant NF-κB inhibitory activity in an Elisa assay (IC₅₀=0.37 μM).     

A novel transformation of 1-exo-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones with sulfoxonium ylide to highly strained 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans

When 1-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (1) were treated with dimethylsulfoxonium methylide, 1-endo isomers (endo-1) gave 1-substituted 3-aroyl-1,2,4a,9b-tetrahydrodibenzofuran-4-ols (2) exclusively as expected. On the other hand, 1-exo isomers (exo-1) underwent a novel transformation to 1-substituted 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans (3), together with 2.     

Furo[3,2-h]isochroman, furo[3,2-h]isoquinoline, isochroman, phenol, pyranone, and pyrone derivatives from the sea fan-derived fungus Penicillium sp. PSU-F40

Nine new fungal metabolites, penicisochromans A-E, penicipyrone, penicipyranone, peniciphenol, and penicisoquinoline, were isolated from the sea fan-derived fungus Penicillium sp. PSU-F40 together with five known compounds. Their structures were determined by spectroscopic analysis. Their antibacterial activity against the standard Staphylococcus aureus ATCC 25923 and methicillin-resistant S. aureus was evaluated.     

Carbamidocyclophanes F and G with anti-Mycobacterium tuberculosis activity from the cultured freshwater cyanobacterium Nostoc sp.

Two new (1 and 2) and three known (3–5) carbamidocyclophanes were isolated from a cultured freshwater cyanobacterium Nostoc sp. (UIC 10274) obtained from a sample collected at Des Plaines, Illinois. Their planar structures and stereoconfigurations were determined by extensive spectroscopic analysis including 1D/2D NMR experiments, HRESIMS as well as CD spectroscopy. Carbamidocyclophane F (1) showed potent anti-Mycobacterium tuberculosis activity in the microplate Alamar blue assay and low-oxygen-recovery assay with MIC values of 0.8 and 5.4 μM, respectively. Carbamidocyclophane F (1) also displayed antimicrobial activities against the gram positive bacteria Staphylococcus aureus and Enterococcus faecalis with MIC values of 0.1 and 0.2 μM, respectively. Carbamidocyclophane F (1) and Carbamidocyclophane G (2) both showed antiproliferative activity against MDA-MB-435 and HT-29 human cancer cell lines with IC₅₀ values in the range from 0.5 to 0.7 μM.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Synthesis of pure stereoisomers of benzo[b]thienyl dehydrophenylalanines by Suzuki cross-coupling. Preliminary studies of antimicrobial activity

Several benzo[b]thienyldehydrophenylalanines were synthesized from pure stereoisomers of the methyl ester of N-(tert-butoxycarbonyl)-β-bromodehydrophenylalanine as an extension of our previously reported method for the synthesis of dehydrotryptophan analogues to dehydrophenylalanine derivatives. The latter were obtained in high yields by N-deprotection and bromination of N,N-bis-(tert-butoxycarbonyl)-(Z)-dehydrophenylalanine using TFA and NBS. This was carried out in two steps or in a one pot procedure resulting in different E/Z ratios. These compounds were coupled under Suzuki cross-coupling conditions [Pd(PPh₃)₄, Na₂CO₃, DME/H₂O] with several boronic benzo[b]thienyl acids in good to high yields maintaining the stereochemistry of the starting materials. The best yields were obtained when the boronic acid was in position 7 of the benzo[b]thiophene and with the E isomer of the brominated dehydrophenylalanine. In some cases it was possible to increase the lower yields by changing the Pd source to PdCl₂(PPh₃)₂. A model dipeptide was prepared coupling a benzo[b]thienyldehydrophenylalanine with the methyl ester of alanine. Preliminary antimicrobial studies were performed with both isomers of one of the β, β-diaryldehydroalanines obtained. The results show that the compounds are selective and very active (very low MICs) against Gram positive bacteria (B. cereus and B. subtilis) the Z-isomer being more active. The compounds are also active against Candida albicans presenting similar MICs.     

Investigation towards an efficient synthesis of benzo[g]isoquinoline-1,5,10(2H)-triones

As part of our research on 2-aza analogues of pentalongin, the active principle of Pentas longiflora Oliv., the first synthesis of 2,3-disubstituted benzo[g]isoquinoline-1,5,10(2H)-triones via 3,4-disubstituted 6-hydroxybenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones as the key intermediates is reported. The latter compounds have been prepared by treating 2-methoxycarbonyl-1,4-naphthoquinone with N-substituted enaminoesters under acidic conditions. These reagents are easily accessible from readily available 1,4-dihydroxy-2-naphthoic acid, β-ketoesters and primary amines. Finally, a short synthesis of substituted benzo[g]isoquinoline-1,5,10(2H)-triones is achieved by an oxidative addition of N-substituted enaminoesters onto methyl 1,4-dihydroxynaphthalene-2-carboxylate.     

Zyzzyanone A, a novel pyrrolo[3,2-f]indole alkaloid from the Australian marine sponge Zyzzya fuliginosa

A new dipyrroloquinone, zyzzyanone A 1, having a pyrrolo[3,2-f]indole-4,8(1H,7H)-dione skeleton, was isolated from the Australian marine sponge Zyzzya fuliginosa, along with the known pyrroloquinoline alkaloids, makaluvamines C, E, G, H, and L, and damirones A and B. The structure of 1 was determined by spectroscopic data. Zyzzyanone A 1 shows moderate cytotoxic activity against mouse Ehrlich carcinoma cells (IC₅₀ 25 μg/mL), inhibits the cell division of fertilized sea urchin eggs at a concentration of 25 μg/mL, and exhibits UV-A and UV-B absorbing activity.     

Synthesis of 4-aza analog of ramelteon: a novel tricyclic 1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyridine derivative as melatonin receptor ligand

The 4-aza analog of ramelteon (−)-1, a novel tricyclic 1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyridine derivative, was synthesized via the intramolecular inverse electron demand Diels-Alder reaction followed by fluoride-induced desilylation-cyclization.     

New developments in the studies of the reactivity of cyclometallated palladium(II) compounds with homo- ([P,P],[As,As]) and heterobidentate ([P,N],[P,O]) ligands

Treatment of the chloro-bridged dinuclear compounds [{Pd[RC₆H₃C(H)NCy-C2,N]}(μ-Cl)]₂ (R = 4-(COH), 1; R = 5-(COH), 2) with bidentate phosphorus or arsenic diphosphines or diarsine ligands in 1:1 molar ratio gave the dinuclear complexes [{Pd[RC₆H₃C(H)NCy-C2,N](Cl)}₂{μ-(o-Tol)₂P(CH₂)₂P(o-Tol)₂}] (R = 4-(COH), 3; R = 5-(COH), 4), [{Pd[RC₆H₃C(H)NCy-C2,N](Cl)}₂{μ-Ph₂PC₄H₂(NH)CH₂PPh₂}] (R = 4-(COH), 5; R = 5-(COH), 6) and [{Pd[RC₆H₃C(H)NCy-C2,N](Cl)}₂{μ-Ph₂As(CH₂)₂AsPh₂}] (R = 4-(COH), 7; R = 5-(COH), 8) with the homobidentate [P,P] and [As,As] ligands in a bridging mode. Treatment of 1 and 2 with the aminophosphine Ph₂P(CH₂)₂NH₂ yields the dinuclear complexes [{Pd[RC₆H₃C(H)NCy-C2,N](Cl)}₂{μ-Ph₂P(CH₂)₂NH₂}] (R = 4-(COH), 9; R = 5-(COH), 10). The analogous reactions carried out in a 1:2 molar ratio, in the presence of NH₄PF₆ or NaClO₄, gave the mononuclear compounds [Pd{RC₆H₃C(H)NCy-C2,N}{(o-Tol)₂P(CH₂)₂P(o-Tol)₂-P,P}][PF₆] (R = 4-(COH), 11; R = 5-(COH), 12), [Pd{RC₆H₃C(H)NCy-C2,N}{Ph₂PC₄H₂(NH)CH₂PPh₂-P,P}][ClO₄] (R = 4-(COH), 13; R = 5-(COH), 14) and [Pd{RC₆H₃C(H)NCy-C2,N}{Ph₂As(CH₂)₂AsPh₂-As,As}][ClO₄](R = 4-(COH), 15; R = 5-(COH), 16), with the [P,P] and [As,As] ligands chelated to the palladium atom.Treatment of 2 with Ph₂P(CH₂)₃NH₂ in a 1:2 molar ratio in acetone in the presence of NH₄PF₆ afforded the mononuclear compound [Pd{5-(COH)C₆H₃C(H)NCy-C2,N}{Ph₂P(CH₂)₃N(Me₂)-P,N}][PF₆], 17, via intermolecular condensation between the aminophosphine and the solvent. Condensation was precluded using toluene as solvent to give [Pd{RC₆H₃C(H)NCy-C2,N}{Ph₂P(CH₂)_nNH₂-P,N}][PF₆], (n = 3, R = 5-(COH), 18; n = 2, R = 4-(COH), 19; n = 2, R = 5-(COH), 20). Treatment of 1 and 2 with Ph₂P(C₆H₄)CHO in a 1:2 molar ratio in the presence of NH₄PF₆ gave the mononuclear complexes [Pd{RC₆H₃C(H)NCy-C2,N}{2-(Ph₂P)C₆H₄CHO-P,O}][PF₆] (R = 4-(COH), 21; R = 5-(COH), 22) with the palladium atom bonded to four different atoms (C, N, P, O) and a chelating [P,O] ligand. The crystal structures of compounds 7, 11, 15 and 21 have been determined by X-ray crystallography.     

Capnosane-type cembranoids from the soft coral Sarcophyton trocheliophorum with antibacterial effects

Nineteen new cembranoids with unusual capnosane skeleton named trocheliophols A–S (1–19) together with four known analogues were isolated from the Chinese soft coral Sarcophyton trocheliophorum. Their structures were determined on the basis of extensive spectroscopic (IR, MS, 1D and 2D NMR) analysis, in addition to the modified Mosher's method, CD and X-ray diffraction for the configuration assignments. The inhibitory effects of the isolated compounds against inflammation-related NF-κB and bacterial pathogens were evaluated. Compounds 8, 9 and 19 exhibited potent inhibitory effects against phytopathogens and human disease-related Gram positive and negative bacteria, while the preliminary structure–activity relationship is discussed.     

2-Allyl-N-benzyl substituted α-naphthylamines as building blocks in heterocyclic synthesis. New and efficient syntheses of benz[e]naphtho[1,2-b]azepine and naphtho[1,2-b]azepine derivatives

A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a-d) and 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepine derivatives (6a-d) have been synthesized from N-allyl-N-benzyl substituted α-naphthylamines (1a-d) by utilizing aromatic amino-Claisen rearrangement, intramolecular Friedel-Crafts alkylation and intramolecular dipolar 1,3-cycloaddition nitrone-olefin reactions.     

A novel synthetic route for the total synthesis of (±)-uleine

In this study, a new synthetic route for the total synthesis of (±)-uleine is described. The important step in the synthesis of this alkaloid consists of an intramolecular cyclization of the D ring of the azocino[4,3-b]indole skeleton. Reduction of (N-methyl){3-β-ethyl-4-oxo-2,3,4,9-tetrahydrospiro[1H-carbazole-1,2′(1,3)dithiolane]-2-yl}-2-acetamide with borane yielded the corresponding (N-methyl){3-β-ethyl-4-hydroxy-2,3,4,9-tetrahydrospiro[1H-carbazole-1,2′(1,3)dithiolane]-2-yl}-2-acetamide, which underwent acid-catalyzed ring closure to produce azocino[4,3-b]indole core. Finally, the synthesis of (±)-uleine was completed through several steps from the azocino[4,3-b]indole core.     

Synthesis, structural characterization, and skeletal rearrangement of dibenzo tricyclo[3.3.0.0]-1,2,5,6-tetrasubstituted octanes

Dibenzo tricyclo[3.3.0.0^2,6]-1,2,5,6-tetrasubstituted octanes, the ‘twisted’ highly strained valence isomers of substituted dibenzo[a,e]cyclooctatetraenes, were synthesized and their structure characterized by single-crystal X-ray analysis. Their skeletal rearrangement was experimentally observed.     

The characterization of (+/-)-anti-benzo[a]pyrene diolepoxide-DNA adducts and (+/-)-anti-dibenzo[a,l]pyrene diolepoxide--DNA adducts in the same DNA sample using solid-matrix phosphorescence

Solid-matrix phosphorescence (SMP) spectra and lifetimes were used to characterize the (±)-anti-benzo[a]pyrene diolepoxide [(±)-anti-B[a]PDE] and (±)-anti-dibenzo[a,l]pyrene diolepoxide [(±)-anti-DB[a,l]PDE] bonded to the same sample of DNA. SMP spectra and lifetimes were also acquired for two samples of DNA that had only (±)-anti-B[a]PDE or (±)-anti-DB[a,l]PDE bonded to the individual samples of DNA. A detailed comparison of the SMP properties was made among the three samples of DNA. The SMP excitation spectra for the (±)-anti-B[a]PDE-DNA and the (±)-anti-DB[a,l]PDE-DNA adducts were very similar. However, the SMP emission spectra of the two DNA adduct systems were very dissimilar with a major emission band for the (±)-anti-B[a]PDE-DNA adducts appearing at 613 nm and for the (±)-anti-DB[a,l]PDE-DNA adducts a major band was at 558 nm. It was possible to selectively use SMP emission wavelengths and obtain a SMP excitation of spectrum of the (±)-anti-DB[a,l]PDE-DNA adducts in the dual adducted DNA sample without the (±)-anti-B[a]PDE-DNA adducts emitting SMP. In addition, it was shown that the SMP emission spectrum of the dual adducted DNA sample could be used to detect both adduct systems in the modified DNA sample. It was demonstrated that the SMP lifetimes could be effectively employed to characterize the dual adducted DNA sample. For example, the SMP decay curve for the (±)-anti-DB[a,l]PDE-DNA adducts could be acquired without any SMP emission from the (±)-anti-B[a]PDE-DNA adducts. Also, ln(SMP intensity) versus time plots were very useful in characterizing the dual adducted DNA sample.     

Short and efficient access to imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives

Access to N-protected or N-free imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives as potential antiviral compounds was achieved in good yields from N-protected 7-amino-8-halo-2-methylimidazo[1,2-a]pyridines by catalytic coupling of terminal acetylenes under mild conditions using [PdCl₂(PPh₃)₂] or [Cu(Phen)(PPh₃)₂]NO₃.     

Application of N,3-diaryl-3-oxo-propanethioamide in synthesis: an efficient and mild domino approach to highly substituted fused chromenones

A convenient and rapid synthesis of hitherto unknown 3-aroyl-4-aryl-2-phenylamino-4H-benzo[g]chromene-5,10-diones in high yield from β-aroyl-thioacetanilide, aromatic aldehyde, and 2-hydroxy-1,4-naphthoquinone via InCl₃ catalyzed one-pot three-component tandem Knoevenagel condensation–Michael addition–intramolecular cyclization–elimination reaction sequence is disclosed for the first time. This domino protocol has been used to obtain highly substituted pyrano[3,2-c]chromen-5(4H)-ones and 7,7-dimethyl-7,8-dihydro-4H-chromen-5(6H)-ones from N,3-diaryl-3-oxo-propanethioamide, aromatic aldehyde, and 4-hydroxycoumarine or dimedone under mild reaction conditions. A plausible reaction mechanism is proposed. The 4H-pyrano[3,2-c]chromen-5-one and 7,7-dimethyl-7,8-dihydro-4H-chromen-5(6H)-one derivatives possessing 3-(2-chlorobenzoyl)-2-phenylamino-substituents further cyclized under basic conditions to yield penta-cyclic 7,13-diaryl-5,14-dioxa-13-aza-benzo[a]naphthacen-6,8(7H,13H)-dione and tetra-cyclic 6,12-diaryl-3,3-dimethyl-3,4-dihydro-2H-chromeno[2,3-b]quinolin-1,11(6H,12H)-dione, respectively.     

Polyhydroxylated macrolide isolated from the endophytic fungus Pestalotiopsis mangiferae

A new polyhydroxylated macrolide, named mangiferaelactone (1) was isolated from a solid culture of the endophytic fungus Pestalotiopsis manguiferae, together with ten known compounds [(6S,1′S)-LL-P880α; (6S,1′S,2′R)-LL-P880β; (1′S,2′R)-LL-880γ; (1′R)-dehydropestalotin; (−)-5-carboxylmellein; (−)-5-methylmellein; (−)-5-hydroxylmethylmellein; arabenoic acid; 5,6-dihydro-4-methoxy-2H-pyran-2-one; and the (−)-2-hexylidene-3-methylsuccinic acid]. P. manguiferae was isolated from Hyptis dilatata, a small shrub common in the central region of Panama. The structure of compound 1 was elucidated by a combination of spectroscopic methods (IR, MS, optical rotation, 1D and 2D NMR spectroscopy). The absolute configuration of 1 was established as 4R,7R,8R,9S by application of vibrational circular dichroism (VCD). Compound 1 showed a minimum inhibitory concentration (MIC) of 1.6863 mg/mL against Listeria monocytogenes, and 0.5529 mg/mL against Bacillus cereus. No activity was observed for compound 1 against Plasmodium falciparum or Trypanosoma cruzi; likewise, no cytotoxic activity was observed against A2058 and H522-T1 cells.     

The structures of three new shishididemniols from a tunicate of the family Didemnidae

Three new serinolipid derivatives, shishididemniols C (1), D (2), and E (3), were isolated as antibacterial constituents of a tunicate of the family Didemnidae. Their planar structures were elucidated by interpretation of NMR and MS data, whereas the absolute stereochemistry was determined by chemical conversions. Shishididemniols C (3), D (4), and E (5) exhibited antibacterial activity against the fish pathogenic bacterium Vibrio anguillarum.