Pyrenocine C,A phytotoxin-related metabolite produced by onion pink root fungus,Pyrenochaeta terrestris

The structure of pyrenocine C, a new metabolite isolated from onion pink root fungus, Pyrenochaeta terrestris (Hansen) has been elucidated as (±)-(2′E)-5-(1′-hydroxybut-2′-enyl)-4-methoxy-6-methyl-2-pyrone by spectroscopic methods and chemical correlation with pyrenocine A.     

Synthesis,characterization and cytotoxicity studies of 1,2,3-triazoles and 1,2,4-triazolo [1,5-a] pyrimidines in human breast cancer cells

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is essential for physiological functions of tissues and neovasculature. VEGFR signaling is associated with the progression of pathological angiogenesis in various types of malignancies, making it an attractive therapeutic target in cancer treatment. In the present work, we report the synthesis of 1,4-disubstituted 1,2,3-triazoles and 1,2,4-triazolo[1, 5-a]pyrimidine derivatives via copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and screened for their anticancer activity against MCF7 cells. We identified 1-(2′-ethoxy-4′-fluoro-[1,1′-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole (EFT) as lead cytotoxic agent against MCF7 cell lines with an IC₅₀ value of 1.69?µM. Further evaluation revealed that EFT induces cytotoxicity on Ishikawa, MDA-MB-231 and BT474 cells with IC₅₀ values of 1.97, 4.81 and 4.08?µM respectively. However, EFT did not induce cytotoxicity in normal lung epithelial (BEAS-2B) cells. Previous reports suggested that 1,2,3-triazoles are the inhibitors of VEGFR1 and therefore, we evaluated the effect of EFT on the expression of VEGFR1. The results demonstrated that EFT downregulates the expression of VEGFR1 in MCF7 cells. In summary, we identified a potent cytotoxic agent that imparts its antiproliferative activity by targeting VEGFR1 in breast cancer cells. The novel compound could serve as a lead structure in developing VEGFR1 inhibitors.     

Identification of 2-(2′-fluoro-[1,1′-biphenyl]-2-yl)acetamide as a Sodium Valproate-like broad spectrum anti-epileptic drug candidate

By further optimizing compound A [2′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide], we identified DSP-0565 [2-(2′-fluoro-[1,1′-biphenyl]-2-yl)acetamide, 17a] as a strong, broad-spectrum anti-epileptic drug (AED) candidate. Our efforts mainly focused on finding an alternative polar group for the sulfonamide in order to improve ADME profile of compound A including good metabolic stability and no reactive metabolic production. This led to the identification of biphenyl acetamide as a new scaffold for development of broad-spectrum AED candidates. DSP-0565 showed anti-convulsant activity in various models (scPTZ, MES, 6?Hz and amygdala kindling) with good safety margin, and was therefore selected as a clinical candidate.     

Tetronic acid and diarylpropanes from Iryanthera elliptica

The trunk wood of Iryanthera elliptica Ducke (Myristicaceae) contains, besides 2-(ω-piperonyltridecyl) -4-methylidenetetronic acid (iryelliptin), three biogenetically related compounds: (±)-7,4′-dihydroxy-3′-methoxyflavan, 1-(4′-hydroxy-2′-methoxyphenyl)- 3-(4″-hydroxy-3″-methoxyphenyl)-propane and spiro-[3-methoxy-2,5-cyclohexadien-1.1′-6′,7′- dihydroxy-5′-methoxy-1′,2′,3′,4′-tetrahydronaphthalen]-4-one-(spiroelliptin). Spiroelliptin rearranges upon methylation to 2,2′-trimethylene-3,4,5,4′,5′-penta-methoxybiphenyl.     

Phenolic derivatives from Wigandia urens with weak activity against the chemokine receptor CCR5

Three compounds, 2,3-dihydroxy-4-methoxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran (1), 8-methoxy-2-methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-6-ol (2) and 4-methoxy-3-(3-methyl-2-butenyl)-benzoic acid (3), have been isolated from Wigandia urens. The structures of compounds 1, 2 and 3 were determined from spectroscopic data and showed activity in a CCR5 assay with IC(50) values of 33, 46 and 26 muM respectively.     

Furanocoumarins from Dorsteniafoetida

The linear furanocoumarins 5-(2,3-epoxy-3-methyl-butoxy)-chalepensin, 5-methoxy-3-(3-methyl-2,3-dihydroxybutyl)-psoralen-diacetate (7), 5-methoxy-3-[3-(β-d-glucopyranosyloxy)-2-acetyloxy-3-methyl-butyl]-psoralen and 5-(3-methyl-2,3-dihydroxybutyloxy)-3-[3-(β-d-glucopyranosyloxy)-2-hydroxy-3-methyl-butyl]-psoralen, and the coumarin derivative 7-hydroxy-5-methoxy-6-carboxymethyl-3-[3-(β-d-glucopyranosyloxy)-2-hydroxy-3-methyl-butyl]-coumarin were isolated from the leaves of Dorstenia foetida (Moraceae) along with the known compounds psoralen, bergapten, isopimpinellin, phellopterin, 5-methoxychalepensin and turbinatocoumarin. Further furanocoumarins were characterized by ESI-MS/MS investigations. The nonpolar extracts of D. foetida exhibit antifungal, antibacterial and cytotoxic activity, however, no anthelminthic activity.     

Lactones,flavonoids and benzophenones from Garcinia conrauana and Garcinia mannii

Two novel lactones have been isolated from the stem barks of Garcinia conrauana and G. mannii. The major component of the bark of G. conrauana was identified as 3-(3$\text{,}\text{?}$ 3″-dimethylallyl)-conrauanalactone [4-hydroxy-3-(3″, 3″-dimethylallyl)-6-pentadecylpyran- 2-one] by comparison of spectral data of the isolated compound and two methylethers with that obtained for the previously isolated conrauanalactone. A minor component of the bark of G. mannii was tentatively identified as 3-α-hydroxy-5-(heptadec-8′-enyl)-tetrahydro- furan-2-one on the basis of spectral data from the isolated compound and its monoacetate. The distributions of biflavonoids and related compounds and benzophenones in the stem bark, heartwood, seeds and leaves of the two species are reported.     

Bicyclo[3,2,1]octanoid,neolignans from Aniba simulans

Six bicyclo[3,2,1]octanoid neolignans, isolated from the benzene extract of Aniba simulans Allen (Lauraceae) trunk wood, are shown to derive from two basic structures: 1-allyl-8-hydroxy-6-(3′-methoxy-4′,5′-methylenedioxyphenyl)-7-methyl-3-oxobicyclo[3,2,1]octane, substituted by 4-hydroxy, 4-hydroxy-5-methoxy, 4-methoxy or 4,5-dimethoxy groups; and 1-allyl-8-hydroxy-6-(3′-methoxy-4′,5′-methylenedioxyphenyl)-7-methyl-4-oxobicyclo[3,2,1]oct-2-ene, substituted by 3-hydroxy or 3-hydroxy-5-methoxy groups. The structural proposals are based on spectral data, interconversions synthesis of a derivative from the known (2R,3S,3aS)-3a-allyl-5-methoxy-2-(3′-methoxy,4′,5′-methylenedioxyphenyl)-3-methyl-2,3,3a,6-tetrahydro-6-oxobenzofuran.     

Neolignans from an Aniba species

A benzene extract of the trunk wood of an Aniba species contained 3a-allyl-2-aryl-5-methoxy-3-methyl-2,3,3a,6-tetrahydro-6-oxobenzofurans which may be responsible, through sequential Cope, retro-Claisen and Claisen rearrangements respectively for the formation of the co-occurring 5-allyl-2-aryl-5-methoxy-3-methyl-2,3,5,6-tetrahydro-6-oxobenzofurans; the 6-O-allyl-2-aryl-5-methoxy-3-methyl-2,3-dihydrobenzofurans and the 7-allyl-2-aryl-6-hydroxy-5-methoxy-3-methyl-2,3-dihydrobenzofurans. The examination of the stereochemistry of these products led to the formulation of burchellin, previously isolated from Aniba burchellii Kostermans, as (2S,3S,3aR)-3a-allyl-5-methoxy-2-piperonyl-3-methyl-2,3,3a,6-tetrahydro-6-oxobenzofuran. The structure 1-allyl-4,8-dihydroxy-7-(3-methoxy-4,5-methylenedioxyphenyl)-6-methyl-3-oxobicyclo[3,2,1]octane is tentatively proposed for an additional neolignan.     

Synthesis of novel spiro[pyrazolo[4,3-d]pyrimidinones and spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3′-indoline]-2′,4(3H)-diones and their evaluation for anticancer activity

An efficient and novel method for the preparation of spiro[pyrazolo[4,3-d]pyrimidin]-7′(1′H)-ones by the condensation of 4-amino-1-methyl-3-propylpyrazole-5-carboxamide with ketones under mild conditions using catalytic InCl₃ was reported. This method has been extended for the synthesis of novel spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3′-indoline]-2′,4(3H)-dione which are having potential applications in medicinal chemistry. All the synthesized compounds were evaluated for their anti-proliferative properties in vitro against cancer cell lines and several compounds were found to be active. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules.     

Synthesis of dihydrochalcones of Myrica gale

4,4,6-Trimethyl-2-(3-phenylpropionyl)cyclohexane-1,3,5-trione, 2′-hydroxy-4′,6′-dimethoxy-3′-methyldihydrochalcone, 2′,6′-dihydroxy-4′-methoxy-3′,5′-dimethyldihydrochalcone and 2,2,5-trimethyl-4(3-phenylpropionyl)cyclopent-4-ene-1,3-dione, constituents of Myrica gale, have been synthesized.     

Deacylation of carcinogenic 5-nitrofuran derivatives by mammalian tissues

The deacylations of N-[4-(5-nitro-2-furyl)-2-thiazolyl] fonnamide (FANFT), N-[4-(5-nitro-2-furyl)-2-thiazolyl] acetarnide (NFTA) and formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl] hydrazide (FNT) by liver, kidney, small intestines and stomach of mouse, rat, hamster and guinea pig were investigated. FANFT was deformylated to 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT). FANFT formamidase activity was higher in the liver and small intestines of mouse, hamster and guinea pig, and small intestines and stomach of rat. There was no detectable FANFT formamidase activity in the stomach of the mouse and hamster. Neither NFTA nor FNT was deacylated by the rodent tissue homogenates studied. It is suggested that (1)4 ANFT is a metabolite of FANFT but not NFTA; (2) 2-hydrazino-4-(5-nitro-2-furyl)thiazole (HNFT) may not be a metabolite of FNT; and (3) the induction of tumors by FANFT, NFTA and FNT may not be due to a common carcinogenic metabolite, although these chemicals demonstrate similar organ specificities in some of these rodents.     

Neolignans from Nectandra miranda

Seven neolignans, isolated from a C₆H₆ extract of Nectandra miranda (Lauraceae) trunk wood, included the hitherto undescribed (2S, 3S, 3aS)- and (2S, 3S, 3aR)-5-allyl-3a-methoxy-2-(3′, 4′, 5′-trimethoxyphenyl)-3-methyl-2, 3, 3a, 6-tetrahydro-6-oxobenzofurans (respectively mirandin-A and mirandin -B), 7-allyl-6-hydroxy-5-methoxy-2-(3′, 4′, 5′-trimethoxyphenyl)-3-methylbenzofuran and (2R, 3R)-7-methoxy-2-(3′, 4′, 5′-trimethoxyphenyl)-3-methyl-5 -(E)-propenyl-2, 3-dihydrobenzofuran (licarin C).     

New flavans isolated from the leaves and stems of Cratylia mollis (Leguminosae)

Cratylia mollis Mart ex. Benth is a species belonging to the Leguminosae family that exists throughout South America, and it is one of the most abundant plants in northeastern Brazil, especially in the semiarid region. This plant is popularly known as “camaratu” and “camaratuba”, and the leaves and stems of this species are used as a substitute for cattle's alimentation during the dry season. The chemical investigation of the methanolic extract from leaves and stems of C. mollis led to the isolation of new flavans named 4,2′,3′-trihydroxy-4′-methoxy-6,7-(methylenedioxy) isoflavan, 7,2′-dihydroxy-6-methoxyflavan, 7,3′-dihydroxy-6,2′-dimethoxyflavan, 7-hydroxy-6-methoxyflavan, 2′-hydroxy-6,7-(methylenedioxy) flavan, 2R*,3S*-7,2′-dihydroxy-6-methoxy-flavan-3-ol, and 2R*,3S*-7,3-dihydroxy-6,2′-dimethoxyflavan-3-ol and an unusual flavan (11H-benzofuro[3,2-b][1] benzopyran-2-methoxy,3-hydroxy,5a,10a-dihydro) named (3R*,2R*)-3-O-2′-7-hydroxy-6-methoxyflavan. The structures of the new compounds were determined using spectroscopic methods.     

Antiprotozoal activity of bicyclic diamines with a N-methylpiperazinyl group at the bridgehead atom

ω-Aminoacyl and -alkyl derivatives of 4-(4-methylpiperazin-1-yl)bicyclo[2.2.2]octan-2-amines and of 5-(4-methylpiperazin-1-yl)-2-azabicyclo[3.2.2]nonanes were prepared and their activities were examined in vitro against the multiresistant K₁ strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). Some of the newly synthesized compounds showed very promising antiprotozoal activity and selectivity. A few of the alkylamino-2-azabicyclo[3.2.2]nonanes exhibited high antiplasmodial activity, whereas a single bicyclo[2.2.2]octane derivative was the most potent antitrypanosomal compound. The results of the newly synthesized compounds were compared with the activities of already synthesized compounds and of drugs in use. Structure–activity relationships were discussed.     

Chemical constituents of the root bark of Erythrina droogmansiana

Two new compounds namely 7,4′-dihydroxy-2′-methoxy-3′-(3-methylbut-2-enyl)isoflavanone (1) and 5,7,3′-trihydroxy-8-(3-methylbut-2-enyl)-[6′′,6′′-dimethylpyrano(2′′,3′′:4′,5′)]isoflavone (4) were isolated from the root bark of Erythrina droogmansiana together with eight known compounds. Their structures were elucidated on the basis of spectroscopic analyses (1D- and 2D-NMR and ESI-HRMS) and by comparison with literature data. In addition, the correct ¹³C NMR of 5,7,2′,4′-tertahydroxy-8,5′-di-(3-metylbut-2-enyl)isoflavone (6) was assigned. The DPPH free radical scavenging properties of the isolated compounds were evaluated. Compounds 4–7 showed weak to moderate DPPH free radical scavenging activities.     

Reactions of hybrid organotellurium ligands 1-(4-methoxyphenyl telluro)-2-[3-(6-methyl-2-pyridyl)propoxy]ethane (L) and 1-ethylthio-2-[2-thienyltelluro]ethane (L) with mercury (II) bromide: formation of complexes and their decomposition

Two tellurium ligands 1-(4-methoxyphenyltelluro)-2-[3-(6-methyl-2-pyridyl)propoxy]ethane (L¹) and 1-ethylthio-2-[2-thienyltelluro]ethane (L²) have been synthesized by reacting nucleophiles [4-MeO-C₆H₄Te⁻] and [C₄H₃S-2-Te⁻] with 2-[3-(6-methyl-2-pyridyl)propoxy]ethylchloride and chloroethyl ethyl sulfide, respectively. Both the ligands react with HgBr₂ resulting in complexes of stoichiometry [HgBr₂ · L¹/L²] (1/4), which show characteristic NMR (¹H and ¹³C{¹H}). On crystallization of 1 from acetone-hexane (2:1) mixture, the cleavage of L¹ occurs resulting in 4-MeOC₆H₄HgBr (2) and [RTe⁺→HgBr₂]Br⁻ (3) (where R = -CH₂CH₂OCH₂CH₂CH₂-(2-(6-CH₃-C₅H₃N))). The 2 is characterized by X-ray diffraction on its single crystal. It is a linear molecule and is the first such system which is fully characterized structurally. The Hg-C and Hg-Br bond lengths are 2.085(6) and2.4700(7) Å. The distance of four bromine atoms (3.4041(7)-3.546(7) Å) around Hg (cis to C) is greater than the sum of van der Waal’s radii 3.30 Å. This mercury promoted cleavage is observed for an acyclic ligand of RArTe type for the first time and is unique, as there appears to be no strong intramolecular interaction to stabilize the cleavage products. The 4 on crystallization shows the cleavage of organotellurium ligand L² and formation of a unique complex [(EtS(CH₂)₂SEt)HgBr(μ-Br)Hg(Br)(μ-Br)₂Hg(Br)(μ-Br)BrHg(EtS(CH₂)₂SEt)] · 2HgBr₂ (5), which has been characterized by single crystal structure determination and ¹H and ¹³C{¹H} NMR spectra. The elemental tellurium and [C₄H₃SCH₂]₂ are the other products of dissociation as identified by NMR (proton and carbon-13). The cleavage appears to be without any transmetalation and probably first of its kind. The centrosymmetric structure of 5 is unique as it has [HgBr₃]⁻ unit, one Hg in distorted tetrahedral geometry and one in pseudo-trigonal bipyramidal one. The molecule of 5 may also be described as having [(EtSCH₂CH₂SEt)HgBr]⁺ [HgBr₃]⁻ units, which dimerize and co-crystallize with two HgBr₂ moieties. There are very weak Hg?Br interactions between co-crystallized HgBr₂ units and rest of the molecule. [Hg(3)-Br(1)/Hg(3)-Br(4) = 3.148(1)/3.216(1) Å]. The bridging Hg?Br distances, Hg(2)-Br(4)′, Hg(2)′-Br(4) and Hg(1)-Br(2), are from 2.914(1) to 3.008(1) Å.     

Solubilization of High-Affinity, Guanine Nucjeotide-Sensitive μ-Opioid Receptors from 7315c Cell Membranes

Abstract: High-affinity μ-opioid receptors have been solubilized from 7315c cell membranes. Occupancy of the membrane-associated receptors with morphine before their solubilization in the detergent 3-[(3-cholamidopropyl) dimethyl]-1-propane sulfonate was critical for stabilization of the receptor. The solubilized opioid receptor bound [³H]-etorphine with high affinity (K_D= 0.304 ± 0.06 nM; B_max= 154 ± 33 fmol/mg of protein). Of the membrane-associated [³H]etorphine binding sites, 40 ± 5% were recovered in the solubilized fraction. Both μ-selective and non-selective enkephalins competed with [³H]etorphine for the solubilized binding sites; in contrast, 5- and K-opioid enkephalins failed to compete with [³H]etorphine for the solubilized binding sites at concentrations of <1 μM.The μ-selective ligand [³H][D-Ala²,A/-Me-Phe⁴,Gly⁵-ol]enkephalin also bound with high affinity (K_D= 0.79 rM; B_max= 108±17 fmol/mg of protein) to the solubilized material. Of the membrane-associated [³H][D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin binding sites, 43 ± 3% were recovered in the solubilized material. Guanosine 5′-O-(3-thiotriphosphate), GTP, and guanosine 5′-O-(2-thiodiphosphate), but not adenylylimidodiphosphate, diminished [³H][D-Ala²,N-Me-Phe⁴,Gly⁵-ol]enkephalin binding in a concentration-dependent manner. Finally, μ-opioid receptors from rat brain membranes were also solubilized in a high-affinity, guanine nucleotide-sensitive state if membrane-associated receptors were occupied with morphine before and during their solubilization with the detergent 3-[(3-cholamidopropyl) dimethyl]-1-propane sulfonate.     

Phytochemicals from the stem wood of Sorbus lanata (D. Don.) Schauer

Three new phenolic compounds, sorlanin (4-(3-(hydroxymethyl)-5-methoxy-7-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-2-methoxyphenol, 1), sorbanin (2-((3,5-dimethoxy-[1,1′-biphenyl]-4-yl)oxy)-1-(4-hydroxy-3-methoxyphenyl)propane-1,3-diol, 2) and sorbalanin (4-(3-(hydroxymethyl)-5,6-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxino[2,3-g]benzofuran-2-yl)-2-methoxyphenol, 3), together with eight known compounds, polystachyol (4), isolariciresinol (5), dihydrodehydrodiconiferyl alcohol (6), tuberculatin (7), ovafolinin E (8), aucuparin (9), 2′-methoxyaucuparin (10), and tetracosyl-3-(3,4-dihydroxyphenyl)acrylate (11), were isolated from Sorbus lanata. The structures of these phytoconstituents were elucidated through extensive spectroscopic techniques, including UV, IR, 1D and 2D NMR, ESI-MS and HRESI-MS experiments. All the compounds except 9 and 10 were isolated for the first time from the genus Sorbus. The isolated compounds were also tested in DPPH radical scavenging reaction where compounds 6, 7, 10 and 11 showed significant activities with IC₅₀ values of 9.2, 11.7, 23.0 and 33.7 μM, respectively.     

Macrophyllin,a neolignan from Licaria macrophylla

The trunk wood of Licaria macrophylla (A. C. Smith) Kosterm. (Lauraceae) contains, in addition to sitosterol, terpene (borneol) and sesquiterpene (nerolidol, elemol) alcohols, a novel neolignan, macrophyllin, for which the structure of 3-allyl-8-hydroxy-1,5-dimethoxy-7-methyl-4(or 2)-oxo-6-(3′,4′-methylenedioxy-5′-methoxyphenyl)-bicyclo [3,2,1] oct-2(or 4)-ene is proposed.