Specific methylation and epoxidation of sinenxan A by Mucor genevensis and the multi-drug resistant tumor reversal activities of the metabolites

Mucor genevensis were used to bioconvert sinenxan A [2α,5α,10β,14β-tetraacetoxy-taxa-4(20),11-diene], a taxoid isolated from callus tissue cultures of Taxus spp., and 10 metabolites were obtained. On the basis of chemical and spectroscopic data analyses, their structures were determined as 10β-methoxy-2α,5α,14β-triacetoxy-taxa-4(20),11-diene (2), 10β-hydroxy-2α,5α,14β-triacetoxy-taxa-4(20),11-diene (3), 2α,5α,10β,14β-tetraacetoxy-4β,20-epoxy-taxa-11(12)-ene (4), 6α-hydroxy-2α,5α,10β,14β-tetraacetoxy-taxa-4(20),11-diene (5), 9α-hydroxy-2α,5α,10β,14β-tetraacetoxy-taxa-4(20),11-diene (6), 10β-hydroxy-2α,5α,14β-triacetoxy-4β,20-epoxy-taxa-11(12)-ene (7), 6α,10β-dihydroxy-2α,5α,14β-triacetoxy-taxa-4(20),11-diene (8), 6α-hydroxy-2α,5α,10β,14β-tetraacetoxy-4β,20-epoxy-taxa-11(12)-ene (9), and 9α,10β-dihydroxy-2α,5α,14β-triacetoxy-taxa-4(20),11-diene (10), and 9α,10β-O-(propane-2,2-diyl)-2α,5α,14β-triacetoxy-taxa-4(20),11-diene (11). Among them, metabolites 2, 4, and 9 were three new compounds. The three major metabolites 2, 3, and 4 along with 1 were pharmacologically evaluated for their multi-drug resistance (MDR) reversal activities towards taxol-resistant A549 tumor cells, and the results showed that 4 possessed about two-fold activity as verapamil, while 2, and 3 possessed lower activity than verapamil and 1.     

Biotransformation of chinensiolide B and the cytotoxic activities of the transformed products

Biotransformation of chinensiolide B, 10α-hydroxy-1α,5α,15-H-3-oxoguaia-11(13)-en-6α,12-olide (1), yielded three selectively reduced products, 3β,10α-dihydroxy-1α,5α,15α-H-guaia-11(13)-en-6α,12-olide (2), 3α,10α-dihydroxy-1α,5α,15α-H-guaia-11(13)-en-6α,12-olide (3), and 3β,10α-dihydroxy-1α,5α,11β,15α-H-guaia-6α,12-olide (4) by the cell suspension cultures of Catharanthus roseus. 2 and 3 were also obtained from 1 incubated with cell cultures of a fungus Abisidia coerulea IFO 4011 and Platycodon grandiflorum, respectively. Among them, 2, 3 are two new compounds. The three products, 2–4, along with 1 were preliminarily evaluated for their in vitro cytotoxic activity against 3 cell lines (HepG2, WI-38 and VA-13) and all showed potent inhibitory effects on the cell proliferation. Of the four compounds, 3 was the most toxic to the three cell lines tested with IC₅₀ values of 22.7, 0.33 and 3.30 μM, respectively.     

Biotransformation of 20(S)-protopanaxadiol by Mucor spinosus

Biotransformation of 20(S)-protopanaxadiol (1) by the fungus Mucor spinosus AS 3.3450 yielded eight metabolites (2–9). On the basis of NMR and MS analyses, the metabolites were identified as 12-oxo-15α,27-dihydroxyl-20(S)-protopanaxadiol (2), 12-oxo-7β,11α,28-trihydroxyl-20(S)-protopanaxadiol (3), 12-oxo-7β,28-dihydroxyl-20(S)-protopanaxadiol (4), 12-oxo-15α,29-dihydroxyl-20(S)-protopanaxadiol (5), 12-oxo-7β,15α-dihydroxyl-20(S)-protopanaxadiol (6), 12-oxo-7β,11β-dihydroxyl-20(S)-protopanaxadiol (7), 12-oxo-15α-hydroxyl-20(S)-protopanaxadiol (8), and 12-oxo-7β-hydroxyl-20(S)-protopanaxadiol (9), respectively. Among them, 2–5, 7, and 8 are new compounds. These results indicated that M. spinosus could catalyze the specific C-12 dehydrogenation of 20(S)-protopanaxadiol, as well hydroxylation at different positions. These biocatalytic reactions may be difficult for chemical synthesis. The biotransformed products showed weak in vitro cytotoxic activities.     

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.     

A study of the reactivity and structure of cyclic α,β-unsaturated Fischer-type carbene complexes

Cycloaddition reactions with α,β-unsaturated carbene complexes of the Fischer-type bearing the carbene carbon atom and the double bond incorporated in the same ring are described. Pentacarbonyl(2H-benzopyran-2- ylidene)chromium(0) complexes (2a-c) and pentacarbonyl(4-methoxy-3,3-dimethyl-2-oxacyclopentylidene)- chromium(0) (3) show a rather low reactivity towards 1,3-dipoles and 1,3-dienes. The reactions with diazomethane are regioselective but not chemoselective; compounds 2 and 3 show two sites of attack: the α,β carbon-carbon and the carbon-metal double bond. The crystal and molecular structures of 2a and 3 have been elucidated by single crystal X-ray analysis. Crystals of 2a are monoclinic, space group P2₁/c, a=7.614(3), b=14.033(3), c=12.766(3) Å, β=95.24°, V=1358.3(7) Å Z=4; crystals of 3 are triclinic, space group P , a=6.553(1), b=9.408(1), c=10.620(1) Å α=92.70(1), β=92.30(1), γ=92.12(1)°, V=653.0(1), ų, Z=2. Final agreement indices for 2a and 3 are R=0.034 and 0.033, respectively. Vibrational properties of the Cr(CO)₅ moiety were interpreted by FT-IR and FT-Raman spectroscopy. Electronic spectra and π electron distribution were interpreted by resonance Raman spectroscopy.     

A new route for the synthesis of Streptococcus pneumoniae 19F and 19A capsular polysaccharide fragments avoiding the β-mannosamine glycosylation step

The recently described [Attolino, E.; Bonaccorsi, F.; Catelani, G.; D’Andrea, F. Carbohydr. Res. 2008, 343, 2545–2556.] β-d-MaNAcp-(1→4)-β-d-Glcp thiophenyl glycosyl donor 3 was used in α-glycosylation reactions of OH-2 and OH-3 of the suitably protected p-MeO-benzyl α-l-rhamnopyranoside acceptors 7 and 8. Glycosylation of the axial OH-2 of 7 took place in high yield (76%) and with acceptable stereoselectivity (α/β = 3.4) leading to the protected trisaccharide α-11, corresponding to the repeating unit of Streptococcus pneumoniae 19F. The same reaction on equatorial OH-3 of acceptor 8 gave the trisaccharide α-15, a constituent of the repeating unit of S. pneumoniae 19A, but in lower yield (41%) and without stereoselection (α/β = 1:1.3). Utilizing the introduced orthogonal protection of OH-1 and OH-4″, the trisaccharide α-11 was transformed into a trisaccharide building block suitable for the synthesis of its phosphorylated oligomers.     

Synthesis and biological activity of O-(N-acetyl-β-muramoyl-l-alanyl-d-isoglutamine)-(1→6)-2-acylamino-2-deoxy-d-glucoses

Benzoylation of benzyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-α-d-glucopyranoside, benzyl 2-deoxy-2-(dl-3-hydroxytetradecanoylamino)-4,6-O-isopropylidene-α-d-glucopyranoside, and benzyl 2-deoxy-4,6-O-isopropylidene-2-octadecanoylamino-β-d-glucopyranoside, with subsequent hydrolysis of the 4,6-O-isopropylidene group, gave the corresponding 3-O-benzoyl derivatives (4, 5, and 7). Hydrogenation of benzyl 2-acetamido-4,6-di-O-acetyl-2-deoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-α-d-glucopyranoside, followed by chlorination, gave a product that was treated with mercuric actate to yield 2-acetamido-1,4,6-tri-O-acetyl-2-deoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-β-d-glucopyranose (11). Treatment of 11 with ferric chloride afforded the oxazoline derivative, which was condensed with 4, 5, and 7 to give the (1→6)-β-linked disaccharide derivatives 13, 15, and 17. Hydrolysis of the methyl ester group in the compounds derived from 13, 15, and 17 by 4-O-acetylation gave the corresponding free acids, which were coupled with l-alanyl-d-isoglutamine benzyl ester, to yield the dipeptide derivatives 19–21 in excellent yields. Hydrolysis of 19–21, followed by hydrogenation, gave the respective O-(N-acetyl-β-muramoyl-l-alanyl-d-isoglutamine)-(1→6)-2-acylamino-2-deoxy-d-glucoses in good yields. The immunoadjuvant activity of these compounds was examined in guinea-pigs.     

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.     

A new ecdysteroid and other constituents from two Dioscorea species

Phytochemical investigation of the rhizome of Dioscorea dumetorum has led to the isolation by several chromatographic steps on normal and reversed phase silica gel of a new ecdysteroid, (20R)-5β,11α,20-trihydroxyecdysone (1), and two known ecdysteroids, ajugasterone C (2) and herkesterone (3). Their structures were determined by spectroscopic methods including 1D- and 2D-NMR (COSY, TOCSY, HSQC and HMBC). This is the first report on the occurrence of phytoecdysteroids in the Dioscoreaceae family. These compounds were devoid of antifungal activity against three Candida species (Candida albicans, Candida glabrata and Candida tropicalis, MIC > 200 μg/ml).     

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.     

A chemosystematically significant 6,8,11-trihydroxygermacrane derivative from the New Zealand Apiaceae Anistome pilifera

Roots of Anisotome pilifera yielded typical Apiaceae compounds 6,7-dimethoxy-coumarin 1 and falcarindiol 2, plus the irregular diterpenes anisotomenoic acid 3 and anisotomene alcohol 4. The new germacrane derivative 8-O-senecioyl-6β,8α,11-trihydroxygermacra-1(10)E,4E-diene 5 was also isolated and the structure established by means of high resolution mass spectrometry and 1-D and 2-D NMR spectroscopy. Distribution and chemosystematic significance of 6,8-dihydroxygermacra-1(10)E,4E-dienes and 6,8,11-trihydroxygermacra-1(10)E,4E-dienes are discussed. Additionally, leaves of A. pilifera yielded chlorogenic acid 6 and high amounts of luteolin 7-O-α- -rhamnosyl(1→6)-β- -glucoside 7.     

Metal dependent coordination of biomolecular ligand: X-ray crystal structures of copper, cobalt and calcium complexes of (3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinic acid) 5-phosphate, an oxidized pyridoxal 5-phosphate

X-ray crystal analyses of divalent copper, cobalt and calcium complexes of monoanionic (3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinic acid) 5-phosphate (L₁C₈H₉NO₇P⁻) revealed the chemical compositions of Cu ---L·3H₂O(1), Co ---L·5H₂O(2) and Ca·L₂·7H₂O (3) and the coordination structures which depend on the coordination abilities and chemical properties of the respective metal ions. Although 1 and 2 crystals showed similar features, i.e., presence of the metal ion at the crystallographic center of symmetry and octahedral six-coordination, the patterns of coordination with the ligand molecules differed. While direct coordination to the L carboxyl oxygen was observed in 1 crystals, all ligation positions in 2 crystals were occupied by water molecules. On the other hand, 3 crystals formed a pentagonal bipyramidal structure (seven-coordination), where oxygens of L phosphates and water molecules coordinated to the calcium ion. Each of the complex structures showed characteristic molecular packing depending on the pattern of coordination to the respective metal ion. L is monoanionic in all complex crystals, where the phosphate and carboxyl groups are deprotonated and pyridine nitrogen is protonated, and is neutralized by each metal ion. Crystal data: 1, monoclinic, space group P2₁/c, A = 5.4129(6), B = 10.515(2), C = 22.770(2) Å, β = 91.853(9)°, Z = 4, R = 0.0404 for 1834 observed reflections; 2, triclinic, space group

Full-size image

, c = 6.789(3) Å, α = 96.84(3), β = 109.10(3), γ = 100.50(2)°, Z = 2, R = 0.0684 for 1605 observed reflections; 3, triclinic, , a = 10.069(2), B = 14.501(3), c = 10.051(1) Å, α = 100.75(1), β = 97.28(2), γ = 76.18(2)°, Z = 2, R = 0.0540 for 3637 observed reflections.     

2-(3′-Hydroxypropylidene)-1α-hydroxy-19-norvitamin D compounds with truncated side chains

Our recent studies with 2-(3′-hydroxypropylidene) analogs of 1α,25-dihydroxy-19-norvitamin D₃ showed that this 2-substituent creates compounds with very potent biological activity. In the continuing search for vitamin D compounds with selective activity profiles, we prepared a series of 1α-hydroxy-19-norvitamin D analogs characterized by the presence of a 3′-hydroxypropylidene substituent at C-2 and a truncated side chain. These vitamin D compounds were efficiently prepared using convergent syntheses. The C,D-fragments, namely the Grundmann ketones 19, 20, 27, 36 and 37 were synthesized from the known 8β-benzoyloxy-22-aldehydes 12 and 29. These hydrindanones were subjected to Lythgoe type Wittig–Horner coupling with phosphine oxide 21, prepared by us previously, and after hydroxyl deprotection the set of 19-norvitamins 7–11 was successfully obtained. According to our expectations, all analogs (with an exception of the 20R-compound 7) have pronounced in vitro activity. When compared to the natural hormone 1α,25-(OH)₂D₃ (1), they show the same or only slightly reduced affinity for the vitamin D receptor while being similarly effective as 1 in differentiation of HL-60 cells into monocytes.     

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.     

Linear sesterterpenes from the Caribbean sponge Thorecta horridus with inflammatory activity

Two new linear sesterterpenes 1 and 2, containing an α,β-unsaturated γ-lactone ring, have been isolated from the Caribbean sponge Thorecta horridus, Hyatt 1877 (F. Thorectidae). The structures of the two new metabolites were established on the basis of spectral data including 2D NMR experiments. Compound 1 exhibits inflammatory activity.Structures of two new linear sesterterpenes 1 and 2 from the sponge Thorecta horridus, determined through HREIMS, 1D and 2D NMR experiments, are reported. Compound 1 exhibits inflammatory activity.     

Synthesis, and carbon-13 n.m.r. study, of O-α- -rhamnopyranosyl-(1→3)-O-α- -rhamnopyranosyl-(1→2)- -rhamnopyranose and O-α- -rhamnopyranosyl-(1→3)-O-α- -rhamnopyranosyl (1→3)- -rhamnopyranose, constituents of bacterial, cell-wall polysaccharides

O-α- -Rhamnopyranosyl-(1→3)- -rhamnopyranose (19) and O-α- -rhamnopyranosyl-(1→2)- -rhamnopyranose were obtained by reaction of benzyl 2,4- (7) and 3,4-di-O-benzyl-α- -rhamnopyranoside (8) with 2,3,4-tri-O-acetyl-α- -rhamnopyranosyl bromide, followed by deprotection. The per-O-acetyl α-bromide (18) of 19 yielded, by reaction with 8 and 7, the protected derivatives of the title trisaccharides (25 and 23, respectively), from which 25 and 23 were obtained by Zemplén deacetylation and catalytic hydrogenolysis, With benzyl 2,3,4-tri-O-benzyl-β- -galactopyranoside, compound 18 gave an ≈3:2 mixture of benzyl 2,3,4-tri-O-benzyl-6-O-[2,4-di-O-acetyl-3-O-(2,3,4-tri-O-acetyl-α- -rhamnopyranosyl)-α- -rhamnopyranosyl]-β- -galactopyranoside and 4-O-acetyl-3-O-(2,3,4-tri-O-acetyl-α- -rhamnopyranosyl)-β- -rhamnopyranose 1,2-(1,2,3,4-tetra-O-benzyl-β- -galactopyranose-6-yl (orthoacetate). The downfield shift at the α-carbon atom induced by α- -rhamnopyranosylation at HO-2 or -3 of a free α- -rhamnopyranose is 7.4-8.2 p.p.m., ≈1 p.p.m. higher than when the (reducing-end) rhamnose residue is benzyl-protected (6.6-6.9 p.p.m.). α- -Rhamnopyranosylation of HO-6 of gb- -galactopyranose deshields the C-6 atom by 5.7 p.p.m. The 1 2-orthoester ring structure [O₂,C(me)OR] gives characteristic resonances at 24.5 ±0.2 p.p.m. for the methyl, and at 124.0 ±0.5 p.p.m. for the quaternary, carbon atom.     

Microbial transformation of isosteviol oxime and the inhibitory effects on NF-κB and AP-1 activation in LPS-stimulated macrophages

Microbial transformation of isosteviol oxime (ent-16-E-hydroxyiminobeyeran-19-oic acid) (2) with Aspergillus niger BCRC 32720 and Absidia pseudocylindrospora ATCC 24169 yielded several compounds. In addition to bioconverting the d-ring to lactone and lactam moieties, 4α-carboxy-13α-hydroxy-13,16-seco-ent-19-norbeyeran-16-oic acid 13,16-lactone (7) and 4α-carboxy-13α-amino-13,16-seco-ent-19-norbeyeran-16-oic acid 13,16-lactam (10), one known compound, ent-1β,7α-dihydroxy-16-oxo-beyeran-19-oic acid (6), and five new compounds, ent-7α-hydroxy-16-E-hydroxyiminobeyeran-19-oic acid (3), ent-1β,7α-dihydroxy-16-E-hydroxyiminobeyeran-19-oic acid (4), ent-1β-hydroxy-16-E-hydroxyiminobeyeran-19-oic acid (5), ent-8β-cyanomethyl-13-methyl-12-podocarpen-19-oic acid (8), and ent-8β-cyanomethyl-13-methyl-13-podocarpen-19-oic acid (9), were isolated from the microbial transformation of 2. Elucidation of the structures of these isolated compounds was primarily based on 1D and 2D NMR, and HRESIMS data, and 3–5 were further confirmed by X-ray crystallographic analyses. Additionally, the inhibitory effects of all of these compounds were evaluated on NF-κB and AP-1 activation in LPS-stimulated RAW 264.7 macrophages. Among the compounds tested, 5 and 10 significantly inhibited NF-κB activation, with 5 showing equal potency to dexamethasone; 3 and 6–9 significantly inhibited AP-1 activation, particularly 8, which showed more inhibitory activity than dexamethasone.     

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.     

m-Alkyl, α,α,α-trifluoroacetophenones: A new class of potent transition state analog inhibitors of acetylcholinesterase

A series of m-alkyl α,α,α-trifluoroacetophenones (1–5) was synthesized and evaluated as inhibitors of acetylcholinesterase from Torpedo california. All ketones (1–5) were found to be potent inhibitors of the enzyme; m-t-butyl α,α,α-trifluoroacetophenone (4) was the most potent inhibitor with a K_i value of 3.7 pM.     

6β,19-Bridged androstenedione analogs as aromatase inhibitors

Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. New 6β,19-bridged steroid analogs of androstenedione, 6β,19-epithio- and 6β,19-methano compounds 11 and 17, were synthesized starting from 19-hydroxyandrostenedione (6) and 19-formylandrost-5-ene-3β,17β-yl diacetate (12), respectively, as aromatase inhibitors. All of the compounds including known steroids 6β,19-epoxyandrostenedione (4) and 6β,19-cycloandrostenedione (5) tested were weak to poor competitive inhibitors of aromatase and, among them, 6β,19-epoxy steroid 4 provided only moderate inhibition (K_i: 2.2 μM). These results show that the 6β,19-bridged groups of the inhibitors interfere with binding in active site of aromatase.