PAF-antagonistic bicyclo[3.2.1]octanoid neolignans from leaves of Ocotea macrophylla Kunth. (Lauraceae)

Di-nor-benzofuran neolignan aldehydes, Δ⁷-3,4-methylenedioxy-3′-methoxy-8′,9′-dinor-4′,7-epoxy-8,3′-neolignan-7′-aldehyde (ocophyllal A) 1, Δ⁷-3,4,5,3′-tetramethoxy-8′,9′-dinor-4′,7-epoxy-8,3′-neolignan-7′-aldehyde (ocophyllal B) 2, and macrophyllin-type bicyclo[3.2.1]octanoid neolignans (7R, 8R, 3′S, 4′S, 5′R)-Δ⁸′-4′-hydroxy-5′-methoxy-3,4-methylenedioxy-2′,3′,4′,5′-tetrahydro-2′-oxo-7.3′,8.5′-neolignan (ocophyllol A) 3, (7R, 8R, 3′S, 4′S, 5′R)-Δ⁸′-4′-hydroxy-3,4,5′-trimethoxy-2′,3′,4′,5′-tetrahydro-2′-oxo-7.3′,8.5′-neolignan (ocophyllol B) 4, (7R, 8R, 3′S, 4′S, 5′R)-Δ⁸′-4′-hydroxy-3,4,5,5′-tetramethoxy-2′,3′,4′,5′-tetrahydro-2′-oxo-7.3′,8.5′-neolignan (ocophyllol C) 5, as well as 2′-epi-guianin 6 and (+)-licarin B 7, were isolated and characterized from leaves of Ocotea macrophylla (Lauraceae). The structures and configuration of these compounds were determined by extensive spectroscopic analyses. Inhibition of platelet activating factor (PAF)-induced aggregation of rabbit platelets were tested with neolignans 1–7. Although compound 6 was the most potent PAF-antagonist, compounds 3–5 showed some activity.     

Prenylated flavonoids of Erythrina lysistemon grown in Egypt

Three prenylated flavonoid derivatives; 5,7,4′-trihydroxy-8-(3-methylbut-2-enyl)-6-(2″-hydroxy-3″-methylbut-3″enyl) isoflavone (isoerysenegalensein E), 5,7,2′-trihydroxy-4′-methoxy-5′-(3″-methylbut-2″-enyl) isoflavanone (lysisteisoflavanone), 5, 4′-dihydroxy-6-(3-methylbut-2-enyl)-2″-hydroxyisopropyl dihydrofurano [4″,5″:8,7] isoflavone (isosenegalensin), together with the four known flavonoids abyssinone V-4′-methylether, alpinumisoflavone, wighteone and burttinone were isolated from the stem bark of Erythrina lysistemon Hutch. (Leguminosae). Structures were elucidated by spectroscopic methods.     

Prenylated flavanones from the twigs of Dorstenia mannii

Investigation of the twigs of Dorstenia mannii gave 6,8-diprenyl-5,7,3′4′-tetrahydroxyflavanone and four new prenylated flavanones, named dorsmanins E-H and characterized as 5,6-7,8-bis-(2,2-dimethylchromano)-3′,4′-dihydroxyflavanone, 7,8-[2″-(1-hydroxy-1-methylethyl)-dihydrofurano]-6-prenyl-5,3′,4′-trihydroxyflavanone, 6,7-[2″-(1-hydroxy-1-methylethyl)dihydrofurano]-8-prenyl-5,3′,4′-trihydroxyflavanone and 6-prenyl-8-(2-hydroxy-3-methylbut-3-enyl)-5,7,3′,4′-tetrahydroxyflavanone, respectively, on the basis of spectral analysis and chemical evidence for the chromano derivative.     

Two chromones from Peperomia vulcanica

Two chromones: 5-hydroxy-2-(14′-(E)-nonadecenyl) chromone (1) and 5-hydroxy-2-[12′-(3″,4″-methylenedioxyphenyl)dodecanyl] chromone (2), together with six known compounds have been isolated from Peperomia vulcanica Baker & C. H. Wright (Piperaceae). Their structures were determined by spectroscopic analysis including 2D NMR techniques.     

Synthesis and evaluation of bioactive naphthoquinones from the Brazilian medicinal plant, Tabebuia avellanedae

A series of naphthoquinones based on the naphtho[2,3-b]furan-4,9-dione skeleton such as (−)-5-hydroxy-2-(1′-hydoxyethyl)naphtho[2,3-b]furan-4,9-dione (1) and its positional isomer, (−)-8-hydroxy-2-(1′-hydoxyethyl)naphtho[2,3-b]furan-4,9-dione (2), which are secondary metabolites found in the inner bark of Tabebuia avellanedae, were stereoselectively synthesized and their biological activities were evaluated in conjunction with those of their corresponding enantiomers. Compound 1 exhibited potent antiproliferative effect against several human tumor cell lines, but its effect against some human normal cell lines was much lower than that of mitomycin. On the other hand, its enantiomer (R)-1 was less active toward the above tumor cell lines than 1. The antiproliferative effect of 2 against all tumor cell lines was significantly reduced. These results indicated the presence of the phenolic hydroxy group at C-5 is of great important for increasing antiproliferative effect. In addition, 1 also showed higher cancer chemopreventive activity than 2, while there were no significant differences between 1 and 2 in antimicrobial activity. Both compounds displayed modest antifungal and antibacterial activity (Gram-positive bacteria), whereas they were inactive against Gram-negative bacteria.     

Synthesis of Neu5Ac- and Neu5Gc-α-(2→6′)-lactosamine 3-aminopropyl glycosides

In order to prepare 3-aminopropyl glycosides of Neu5Ac-α-(2→6′)-lactosamine trisaccharide 1, and its N-glycolyl containing analogue Neu5Gc-α-(2→6′)-lactosamine 2, a series of lactosamine acceptors with two, three, and four free OH groups in the galactose residue was studied in glycosylations with a conventional sialyl donor phenyl [methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-thio- -glycero-α- and β- -galacto-2-nonulopyranosid]onates (3) and a new donor phenyl [methyl 4,7,8,9-tetra-O-acetyl-5-(N-tert-butoxycarbonylacetamido)-3,5-dideoxy-2-thio- -glycero-α- and β- -galacto-2-nonulopyranosid]onates (4), respectively. The lactosamine 4′,6′-diol acceptor was found to be the most efficient in glycosylation with both 3 and 4, while imide-type donor 4 gave slightly higher yields with all acceptors, and isolation of the reaction products was more convenient. In the trisaccharides, obtained by glycosylation with donor 4, the 5-(N-tert-butoxycarbonylacetamido) moiety in the neuraminic acid could be efficiently transformed into the desired N-glycolyl fragment, indicating that such protected oligosaccharide derivatives are valuable precursors of sialo-oligosaccharides containing N-modified analogues of Neu5Ac.     

Derivatives of β- -fructofuranosyl α- -galactopyranoside

De-etherification of 6,6′-di-O-tritylsucrose hexa-acetate (2) with boiling, aqueous acetic acid caused 4→6 acetyl migration and gave a syrupy hexa-acetate 14, characterised as the 4,6′-dimethanesulphonate 15. Reaction of 2,3,3′4′,6-penta-O-acetylsucrose (5) with trityl chloride in pyridine gave a mixture containing the 1′,6′-diether 6 the 6′-ether 9, confirming the lower reactivity of HO-1′ to tritylation. Subsequent mesylation, detritylation, acetylation afforded the corresponding 4-methanesulphonate 8 1′,4-dimethanesulphonate 11. Reaction of these sulphonates with benzoate, azide, bromide, and chloride anions afforded derivatives of β- -fructofuranosyl α- -galactopyranoside (29) by inversion of configuration at C-4. Treatment of the 4,6′-diol 14 the 1,′4,6′-triol 5, the 4-hydroxy 1′,6′-diether 6 with sulphuryl chloride effected replacement of the free hydroxyl groups and gave the corresponding, crystalline chlorodeoxy derivatives. The same 4-chloro-4-deoxy derivative was isolated when the 4-hydroxy-1′,6′-diether 6 was treated with mesyl chloride in N,N-dimethylformamide.     

Synthesis and discovery of autophagy inducers for A549 and H460 lung cancer cells, novel 1-(2'-hydroxy-3'-aroxypropyl)-3-aryl-1H-pyrazole-5-carbohydrazide derivatives

A series of novel 1-(2′-hydroxy-3′-aroxypropyl)-3-aryl-1H-pyrazole-5-carbohydrazide derivatives were synthesized, and the effects of the compounds on A549 cell growth were investigated. The results showed that all of the 1-(2′-hydroxy-3′-aroxypropyl)-3-aryl-1H-pyrazole-5-carbohydrazide derivatives 2 could inhibit the growth of A549 cells in dosage- and time-dependent manners. Typically, compound 2a and 2d induced A549 cells to autophagy but did not cause apoptosis and necrosis in the cells, and 2d had the most autophagy inducing effect in H460 cells. More importantly, 2a and 2d did not inhibit the growth of HUVEC cells.     

Phthalide mono- and dimers from the radix of Angelica sinensis

Phytochemical investigation of the radix of Angelica sinensis has led to the isolation and identification of a new phthalide dimer, (3Z)-(3aR,6S,3′R,8′S)-3a.8′,6.3′-diligustilide (1), along with three known phthalide dimers, including riligustilide (2), levistolide A (3), senkyunolide O (4), and three known phthalide monomers, including 3,9-dihydroxyl-ligustilide (5), (Z)-butylidene phthalide (6), (Z)-ligustilide (7). Their structures were determined by spectroscopic methods including IR, NMR (¹H NMR, ¹³C NMR, COSY, HSQC, HMBC and NOESY) and MS. Meanwhile, the possible biosynthesis pathways of compounds 1 and 5 were hypothesized.     

Conformational properties of Eu(III) complexes of 3,3′; 5,3″-polymethylene bridged derivatives of 2,2′; 6,2″-terpyridine

The complex [Eu(tpy)₃](ClO₄)₃ where TPY=2,2′; 6,2″-terpyridine, has been prepared and reexamined. The complex appears to be stable in acetonitrile solution with respect to decomplexation of the ligands but the addition of water does cause partial replacement of tpy. Analogous complexes have been prepared with 3,3′; 5,3″-polymethylene bridged derivatives of tpy having two or three carbons in the bridge. The bridging enforces a cisoid geometry of the ligand and prohibits its replacement by added water. An X-ray determination was carried out for [Eu(3b)₃](ClO₄)₃, where 3b=3,3′; 5,3″-dimethylene tpy, which crystallizes in the monoclinic space group P2₁/c with a=11.908(4), b=15.768(5), c=29.513(9) Å, β=93.60(2)°, μ=13.5 cm⁻¹ and Z=4. The complex forms a tricapped trigonal prism with each of the ligands adopting the same dl conformation. Variable temperature NMR analysis of the bridged ligand complexes indicates that conformational inversion of the bound ligand is not a concerted process and barriers for inversion of individual methylene units can be estimated from coalescence of the signals from the geminal methylene protons. The luminescence properties of the bridged tpy complexes are similar to the parent unbridged system.     

Isoflavones with unusually modified B-rings and their evaluation as antiproliferative agents

Six novel isoflavone derivatives along with four known isoflavones were isolated from a culture of a highly nickel-resistant strain of Streptomyces mirabilis from a former uranium mining area. The structures of 7-hydroxy-3′,5′-dihydroxyisoflavone (5), 5,7-dihydroxy-3′,5′-dihydroxyisoflavone (6), 2′-hydroxy-3′-methoxygenistein (7), as well as hydroisoflavones A–C (8–10) were elucidated by MS and NMR analyses. Compounds 8–10 feature yet unprecedented types of non-aromatic, hydroxylated B rings, which result from plant isoflavone biotransformation. All new compounds display weak cytotoxic but potent antiproliferative activities. The anti-oestrogenic properties of 8 against MCF-7 human breast cancer cell line (GI₅₀: 6 μM) is even higher than the reference compound genistein.     

Hemiterpene glucosides and other constituents from Spiraea canescens

Five glycosides, 2-(trans-cinnamoyloxy-methyl)-1-butene-4-O-β-d-glucopyranoside (1), 4-(6′-O-trans-cinnamoyl)-(2-hydroxymethyl-4-hydroxy-butenyl-β-d-glucopyranoside (2), 6′′-O-trans-p-coumaroyl-(4-hydroxybenzoyl)-β-d-glucopyranoside (3), 6′-O-(4-methoxy-trans-cinnamoyl) α/β-d-glucopyranose (4) 6′-O-(4′′-methoxy-trans-cinnamoyl)-kaempferol-3-β-d-glucopyranoside (7) along with six known compounds, (+)-isolariciresinol 3a-O-β-d-glucopyranoside (8) (+)-lyoniresinol 3a-O-β-d-glucopyranoside (9), apigenin 7-O-β-d-glucopyranoside (10), quercetin 3-O-β-d-glucopyranoside (11), 6′-O-cinnamoyl-α/β-d-glucopyranose (6) 6’-O-p-coumaroyl-α/β-d-glucopyranose (5) were isolated from the whole plant of Spiraea canescens. Some of these compounds showed potent radical scavenging activity in relevant non-physiological assays. Their structures were determined by NMR spectroscopic and CID mass spectrometric techniques.     

Structure activity relationship exploration of 5-hydroxy-2-(3-phenylpropyl)chromones as a unique 5-HT2B receptor antagonist scaffold

Antagonists for the serotonin receptor 2B (5-HT_2B) have clinical applications towards migraine, anxiety, irritable bowl syndrome, and MDMA abuse; however, few selective 5-HT_2B antagonists have been identified. Previous studies from these labs identified a natural product, 5-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 2) as the first non-nitrogenous ligand for the 5-HT_2B receptor. Studies on 5-HPEC optimization led to the identification of 5-hydroxy-2-(3-phenylpropyl)chromone (5-HPPC, 3), which showed a tenfold improvement in binding affinity over 2 at 5-HT_2B. This study aimed to further improve receptor pharmacology of this unique scaffold. Guided by molecular modeling studies modifications at the C-3′ and C-4′ positions of 3 were made to probe their effects on ligand binding affinity and efficacy. Among the derivatives synthesized 5-hydroxy-2-(3-(3-cyanophenyl)propyl)chromone (5-HCPC, 3d) showed the most promise with a multifold improvement in binding affinity (pK_i = 7.1 ± 0.07) over 3 with retained antagonism.     

1-Methoxy-, 1-deoxy-11-hydroxy- and 11-Hydroxy-1-methoxy-Δ-tetrahydrocannabinols: new selective ligands for the CB2 receptor

Three series of new cannabinoids were prepared and their affinities for the CB₁ and CB₂ cannabinoid recptors were determined. These are the 1-methoxy-3-(1′,1′-dimethylalkyl)-, 1-deoxy-11-hydroxy-3-(1′,1′-dimethylalkyl)- and 11-hydroxy-1-methoxy-3-(1′,1′-dimethylalkyl)-Δ⁸-tetrahydrocannabinols, which contain alkyl chains from dimethylethyl to dimethylheptyl appended to C-3 of the cannabinoid. All of these compounds have greater affinity for the CB₂ receptor than for the CB₁ receptor, however only 1-methoxy-3-(1′,1′-dimethylhexyl)-Δ⁸-THC (JWH-229, 6e) has effectively no affinity for the CB₁ receptor (K_i=3134±110 nM) and high affinity for CB₂ (K_i=18±2 nM).     

Production of 2-(2-phenylethyl) Chromones in Cell Suspension Cultures of <Emphasis Type="Italic">Aquilaria sinensis</Emphasis>

2-(2-Phenylethyl) chromones are the major constituents responsible for the quality of agarwood, which is one of the most valuable non-timber products used as incenses, perfumes, traditional medicines and other products. In this study, cell suspension culture of Aquilaria sinensis (Lour) Gilg was used to monitor the eliciting effects of crude fungal extracts on cell growth and chromones production. Crude extracts of Melanotus flavolivens (B. etc) Sing. prepared with different solvents were used to elicit the production of 2-(2-phenylethyl) chromones in cell suspension cultures of A. sinensis. Four 2-(2-phenylethyl) chromones,␣6,7-dimethoxy-2-(2-phenylethyl) chromone (1), 6,7-dimethoxy-2-[2-(4′-methoxyphenyl)ethyl] chromone (2), 6-methoxy-2-[2-(4′-methoxyphenyl)ethyl] chromone (3) and 6-methoxy-2-(2-phenylethyl) chromone␣(4),␣were detected by LC–MS in the cell suspension culture of A. sinensis elicited with crude extracts of M. flavolivens. Three hundred and seventy eight, 196 and 31 μg g⁻¹ DW of 2-(2-phenylethyl) chromones were obtained in the cell cultures induced by water extracts, 50 and 95% ethanol extracts of M. flavolivens, respectively. The results show that water-soluble materials in the crude extracts are the main components inducing the production of 2-(2-phenylethyl) chromones in the cell cultures.     

Optical resolution of hexamethylbiphenol by cholesterol esterase and porcine pancreas lipase

Both enantiomers of 2,2′-dihydroxy-4,4′,5,5′,6,6′-hexamethybiphenyl (2), a potentially useful chiral synthon, were obtained with >99% ee in high enantioselectivity by cholesterol esterase or porcine pancreas lipase (PPL)-mediated hydrolysis of the corresponding (±)-dipentanoate or (±)-dihexanoate, respectively. Absolute configuration of (S)-3-bromo-2,6′-dimethoxy-4,5,6,2′,3′,4′-hexamethyl-biphenyl (2h) was determined by X-ray analysis.     

First report of Alexandrium taylori and Alexandrium peruvianum (Dinophyceae) in Malaysia waters

The occurrence of Alexandrium taylori and Alexandrium peruvianum is reported for the first time in Malaysia waters. The Malaysian A. taylori isolates were pyriform in shape with a transdiameter range of 36–40 μm and a cell length range of 33–37 μm. The first apical plate (1′) was pentagonal with two distinctive anterior margins. No direct connection between 1′ and the apical pore complex was observed. The posterior sulcal plate (S.p.) was large, elongated and oblique to the right with anterior projections. The ventral pore (vp) was relatively large and situated at a confluence point of 1′, the second apical (2′) and the fourth apical (4′) plates. Cells of A. peruvianum were slightly anteriorly and posteriorly compressed. S.p. had an irregular pentagonal shape, with the anterior margin divided into 2 portions. 1′ was boomerang-shaped with a large and truncated ventral pore in the middle right margin. The anterior right margin of 1′ was straight. The sixth precingular plate (6″) was wider than long. The anterior sulcal plate (S.a.) was triangular and lacked a left portion extension. In laboratory cultures, both A. taylori and A. peruvianum produced paralytic shellfish toxins, with GTX4 and GTX6 as the predominant toxin, respectively. This is the first report of PSP toxins production for both species as well as the occurrences in Malaysia waters.     

Thermomyces lanuginosus lipase-catalyzed regioselective acylation of nucleosides: Enzyme substrate recognition

Substrate recognition of Thermomyces lanuginosus lipase in the acylation of nucleosides was revealed through rational substrate engineering for the first time. T. lanuginosus lipase displayed higher catalytic activities and excellent 5′-regioselectivities (94–>99%) in the acylation of ribonucleosides 1f–1j as compared to those in the acylation of 2′-deoxynucleosides 1a–1e. The higher reaction rates and excellent 5′-regioselectivities might derive from a favorable hydrogen bonding between the 2′-hydroxyl group of 1f–1j and phenolic hydroxyl group of Tyr21 present in the hydrophilic region of the lipase.     

The inactivation of acetylcholinesterase by alpha-terthienyl and ultraviolet light Studies in vitro and in larvae of the mosquito Aedes aegypti

Acetylcholinesterase (EC 3.1.1.7) was inactivated photochemically in solution, in the presence of dissolved terthiophene sensitizers. Alpha-terthienyl (2,2′:5,2″-terthiophene) and its isomers 3,2′:5′,2″- and 3,2′:5′,3″-terthiophenes showed very similar sensitizing properties. With all three terthiophenes, the photosensitization was completely suppressed under anaerobic conditions, and therefore the inactivation process required the presence of oxygen. The enzyme was inactivated in vivo when fourth instar larvae of the mosquito Aedes aegypti were treated with alpha-terthienyl in the presence of long-wavelength ultraviolet light. No inactivation was observed when the organisms were treated with the ultraviolet light alone, with the chemical alone, or with a previously irradiated sample of the chemical. This paper represents the first example of acetylcholinesterase inactivation in vivo by a photoactive insecticide.     

3-(1′,1′-Dimethylbutyl)-1-deoxy-Δ-THC and related compounds: synthesis of selective ligands for the CB2 receptor

The synthesis and pharmacology of 15 1-deoxy-Δ⁸-THC analogues, several of which have high affinity for the CB₂ receptor, are described. The deoxy cannabinoids include 1-deoxy-11-hydroxy-Δ⁸-THC (5), 1-deoxy-Δ⁸-THC (6), 1-deoxy-3-butyl-Δ⁸-THC (7), 1-deoxy-3-hexyl-Δ⁸-THC (8) and a series of 3-(1′,1′-dimethylalkyl)-1-deoxy-Δ⁸-THC analogues (2, n=0–4, 6, 7, where n=the number of carbon atoms in the side chain−2). Three derivatives (17–19) of deoxynabilone (16) were also prepared. The affinities of each compound for the CB₁ and CB₂ receptors were determined employing previously described procedures. Five of the 3-(1′,1′-dimethylalkyl)-1-deoxy-Δ⁸-THC analogues (2, n=1–5) have high affinity (K_i=<20 nM) for the CB₂ receptor. Four of them (2, n=1–4) also have little affinity for the CB₁ receptor (K_i=>295 nM). 3-(1′,1′-Dimethylbutyl)-1-deoxy-Δ⁸-THC (2, n=2) has very high affinity for the CB₂ receptor (K_i=3.4±1.0 nM) and little affinity for the CB₁ receptor (K_i=677±132 nM).

Scheme 3. (a) (C₆H₅)₃PCH₃⁺ Br⁻, n-BuLi/THF, 65°C; (b) LiAlH₄/THF, 25°C; (c) KBH(sec-Bu)₃/THF, −78 to 25°C then H₂O₂/NaOH.