Isolation and identification of the intermediates during pyrazole formation of some carbohydrate hydrazone derivatives

Reaction of the oxidation product of L-ascorbic acid, dehydro-L-ascorbic acid, with o-phenylenediamine, followed by 2,4,6-trichlorophenylhydrazine (3) afforded 3-[1-(2,4,6-trichlorophenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one (4), whose structure was deduced from studying its periodate oxidation, which gave the glyoxal derivative 3-[1-(2,4,6-trichlorophenylhydrazono)glyoxal-1-yl]quinoxalin-2(1H)one (5) that upon reduction afforded 3-[1-(2,4,6-trichlorophenylhydrazono)-2-hydroxyethy-1-yl]quinoxalin-2(1H)one (6). The reaction of 5 with 3 afforded the bishydrazone 3-[1,2-bis(2,4,6-trichlorophenylhydrazono)glyoxal-1-yl]quinoxalin-2(1H)one. The reaction of 5 with acetic anhydride in pyridine afforded the 2,3-dihydrofuro[2,3-b]quinoxaline derivative 2-acetoxy-3-[2-acetyl-2-(2,4,6-trichlorophenyl)hydrazono)]-2,3-dihydrofuro[2,3-b]quinoxaline. Acetylation of 4 with acetic anhydride in pyridine afforded the acyclic diacetate intermediate 3-[3,4-di-O-acetyl-2-deoxy-1-(2,4,6-trichlorophenylhydra-zono)but-2-en-1-yl]quinoxalin-2(1H)one (12), which was also obtained from the reaction of 4 with boiling acetic anhydride. Compound 12 rearranged under the reaction conditions to give the pyrazole derivatives 3-[5-(ace-toxymethyl)-1-(2,4,6-trichlorophenyl)pyrazol-3-yl]quinoxalin-2(1H)one (14) and 2-acetoxy-3-[5-(acetoxymethyl)-1-(2,4,6-trichlorophenyl)pyrazol-3-yl)]quinoxaline (15), as well as the 2,3-dihydrofuro[2,3-b]quinoxaline derivative 2-(2-acetoxyethen-2-yl)-3-[2-(2,4,6-trichlorophenyl)hydrazono]-2,3-dihydrofuro[2,3-b]quinoxaline. Acetylation of 3-[5-(hydroxymethyl)-l-(2,4,6-trichlorophenyl)pyrazol-3-yl]quinoxalin-2(1H)one (16) with acetic anhydride in pyridine or 12 with boiling acetic anhydride afforded 15 and 16, respectively. Treatment of 4 with diluted sodium hydroxide afforded the pyrazolo[2,3-b]quinoxaline (flavazole) derivative 1-(2,4,6-trichlorophenyl)-3-(L-threo-glycerol-1-yl)pyrazolo[2,3-b]quinoxaline whose acetylation afforded the acetyl derivative 3-(2,3,4-tri-O-acetyl-L-threo-glycerol-1-yl)-1-(2,4,6-trichlorophenyl)pyrazolo[2,3-b]quinoxaline. The assigned structures were based on spectral analysis. The activity of compound 4 against hepatitis B virus has been studied.     

Synthesis and in vitro antiproliferative activity of new 11-aminoalkylamino-substituted 5H- and 6H-indolo[2,3-b]quinolines; structure-activity relationships of neocryptolepines and 6-methyl congeners

The present report describes the synthesis and antiproliferative evaluation of certain 11-aminoalkylamino-substituted 5H- and 6H-indolo[2,3-b]quinolines and their methylated derivatives. These 5-Me- and 6-Me-indolo[2,3-b]quinoline derivatives 10-14, 20 were prepared by amination at the C-11 position of the 11-chloro-5-methyl-5H- and 11-chloro-6-methyl-6H-indolo[2,3-b]quinolines with different substituents on the quinoline ring. The 11-aminoalkylaminomethylated 23, the homologue of 11, was prepared from the same intermediate for a further SAR study. These intermediates are accessible from 4-substituted anilines or their N-methylated analogues and methyl indole-3-carboxylate as a counterpart. The in vitro antiproliferative assay indicated that the 5-methylated derivatives 10-14 are more cytotoxic than their respective 6-methylated 6H-indolo[2,3-b]quinoline derivatives 20. Among them, N-(3-aminopropyl)-2-bromo-5-methyl-5H-indolo[2,3-b]quinolin-11-amine 12f was the most cytotoxic with a mean IC(50) value of 0.12 μM against human leukemia MV4-11 cell line, and also exhibited selective cytotoxicities against A549 (lung cancer), HCT116 (colon cancer) cell lines and normal fibroblast BALB/3T3 with IC(50) values of 0.543, 0.274 and 0.869 μM, respectively. The binding constant of products 12f and 20f to salmon fish sperm DNA were also evaluated using UV-vis absorption spectroscopy, indicating intercalation binding with a constant of 2.93×10(5) and 3.28×10(5)Lmol(-1), respectively.     

Synthesis of 3-(alpha- and beta-D-arabinofuranosyl)-6-chloro-1,2,4-triazolo[4,3-b]pyridazine

Di-O-isopropylidene- and O-methanesulfonyl-protected 1-C-(6-chloro-1,2,4-triazolo[4,3-b]pyridazin-3-yl)pentitols were prepared in three to four steps from D-galactose, D-glucose, D-mannose, and 2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose. Acid-catalysed treatment of (1S)- and (1R)-1-C-(6-chloro-1,2,4-triazolo[4,3-b]-pyridazin-3-yl)-2,3:4,5-di-O-isopropylidene-1-O-methanesulfonyl-D-arabinitols in refluxing 1,2-dimethoxyethane furnished 3-(alpha- and beta-D-arabinofuranosyl)-6-chloro-1,2,4-triazolo[4,3-b]pyridazine, respectively. Several structures, including the structure of the 3-(beta-D-arabinofuranosyl)-6-chloro-1,2,4-triazolo[4,3-b]pyridazine, were also determined by single-crystal X-ray diffraction analysis.     

Double-headed acyclo C-nucleoside analogues. Functionalized 1,2-bis-(1,2,4-triazol-3-yl)ethane-1,2-diol

Reaction of L-tartaric acid with thiocarbohydcrazide afforded (1R, 2S)-1,2-bis(4-amino-5-mercapto-1,2,4-triazol-3-yl)-ethane-1,2-diol (3). The functional groups in 3 allowed the construction of fused heterocycles on the 1,2,4-triazole rings, mainly of the 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine type as in 4, 5, 7, 10, 13 and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole type as in 14.     

Synthesis of Modified Nucleotide Building Blocks Containing Electrophilic Groups in the 2′-Position

Abstract

Chemical syntheses of 2′-O-(allyloxycarbonyl)methyladenosine, 2′-O-(methoxycarbonyl)methyladenosine and 2′-O-(2,3-dibenzoyloxy)propyluridine 3′-2-cyanoethyl-N,N-diisopropyl phosphoramidite building blocks are described. These monomers were used successfully to incorporate carboxylic acid, 1,2-diol and aldehyde functionalities into synthetic oligonucleotides.     

Regio- and enantio-selective acetylation of 3,3,3-trifluoro-2-arylpropane-1,2-diols using Candida antarctica lipase

Of nine commercially available lipases, lipase SP 435 from Candida antarctica, showed moderate enantioselectivity (E=17) for acetylation of racemic 3,3,3-trifluoro-2-phenylpropane-1,2-diol, 2, with vinyl acetate in diisopropyl ether (S selectivity). The other eight had low selectivities, with E values below 10. The selectivity and reactivity of SP 435 for 2 was markedly improved in dichloroethane (E=41). Moreover, SP 435 had moderate to high selectivity for the related compounds 3,3,3-trifluoro-2-(1-naphthyl)-propane-1,2-diol, 4, (E=20), 3,3,3-trifluoro-2-(indol-3-yl)propane-1,2-diol, 6, (E=80), and 3,3,3-trifluoro-2-(pyrrol-2-yl)-propane-1,2-diol, 8, (E=17).     

Synthesis and antimicrobial activity of novel 1,4,5-triphenyl-1<Emphasis Type="Italic">H</Emphasis>-imidazol-[1,2,3]-triazole derivatives

Novel 1-phenyl-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole derivatives were synthesized by click chemistry reaction and screened for antimicrobial activity against grampositive and gram-negative bacterial and fungal species. All the compounds were characterized by ¹H and ¹³C NMR, IR, and mass spectral data. The results of antibacterial study indicated that 1-(4-nitrophenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole, 1-(4-(4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)ethanone, 1-(2,6-dichloro-4-nitrophenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole, and 1-(2-methoxy-4-nitrophenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole showed appreciable antibacterial activity while 1-(4-fluorophenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy) methyl)-1H-1,2,3-triazole, 1-(2,6-dichloro-4-nitrophenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole, and 1-(4-methoxyphenyl)-4-((4-(1,4,5-triphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazole emerged as the most potential antifungal agents.     

Metabolism of acetoin in mammalian liver slices and extracts. Interconversion with butane-2,3-diol and biacetyl

1. [(14)C]Acetoin was enzymically synthesized from [(14)C]pyruvate with a pyruvate decarboxylase preparation. Its optical activity was [alpha](20) (d)-78 degrees . 2. Large amounts (1000-fold higher than physiological concentrations) of acetoin were incubated with rat liver mince. Acetoin disappeared but very little (14)CO(2) was evolved. A compound accumulated, which was purified and identified as butane-2,3-diol. Chromatography on borate-impregnated paper indicated the presence of both the erythro and threo forms. 3. Liver extracts capable of interconverting biacetyl, acetoin and butane-2,3-diol were obtained. These interconversions were catalysed by two different enzymes: acetoin dehydrogenase (EC 1.1.1.5) and butane-2,3-diol dehydrogenase (EC 1.1.1.4), previously identified in bacteria. Both required NAD(+) or NADP(+) as cofactors and were different from alcohol dehydrogenase. The equilibrium in both cases favoured the more reduced compound. 4. The activity of butane-2,3-diol dehydrogenase was decreased by dialysis against EDTA: the addition of Co(2+), Cu(2+), Zn(2+) and other bivalent metal ions restored activity. 5. Biacetyl reductase was resolved into multiple forms by CM-Sephadex chromatography and electrophoresis.     

A novel synthesis of acyclonucleosides via allylation of 3-[1-(phenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one

The allylation of 3-[1-(phenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one (1) gave, in addition to the anticipated 1-N-allyl derivative (2), a dehydrative cyclized product, 1-N-allyl-3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]quinoxalin-2-one (4) and its isomeric O-allyl derivative 3. The O-allyl group in 3 underwent acetolysis under acetylation conditions, in addition to the acetylation of the hydroxyl group, to afford 2-acetoxy-3-[5-(acetoxymethyl)-1-phenylpyrazol-3-yl]quinoxaline (8) instead of the O-acetyl derivative of 3. Allylation of the tri-O-acetyl derivative of 1 caused the elimination of a molecule of acetic acid in addition to N-allylation to give 1-N-allyl-3-[3,4-di-O-acetyl-2-deoxy-1-(phenylhydrazono)but-2-en-1-yl]quinoxalin-2-one (11). Hydroxylation of the allyl group gave a glycerol-1-yl acyclonucleoside which can be alternatively obtained by a displacement reaction of the tosyloxy group in 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)glycerol (14), followed by deisopropylidenation. 1-N-(2,3-Dibromopropyl)-3-[5-(hydroxymethyl)-1-(4-bromophenyl)pyrazol-3-yl]quinoxalin-2-one (15) underwent azidolysis to give a 2,3-diazido derivative. The assigned structures were based on spectral analysis. The activity of compounds 2, 4, 6, and 15 against hepatitis B virus was studied.     

Microwave-Assisted Synthesis and Anti-HIV Activity of New Acyclic C-Nucleosides of 3-(D-Ribo-Tetritol-1-yl)-5-Mercapto-1,2,4-Triazoles. Part 1

Microwave-assisted synthesis of novel acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5–12) and the 6-aryl-thiomethyl analogues 25–27 has been described. Deblocking of 5–12 and 25–27 afforded the free acyclic C-nucleosides 13–20, and 28–30, respectively. All of the synthesized compounds showed no inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 6-(3,4-dichlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (6) is a potent inhibitor, in vitro, of the replication of HIV-2. These results suggest that compound 6 should be considered as a new lead in the development of antiviral agent.     

Synthesis, biological evaluation and molecular modeling of 1,2,3-triazole analogs of combretastatin A-1

The synthesis, cytotoxicity, inhibition of tubulin polymerization data and anti-angiogenetic effects of seven 1,5-disubstituted 1,2,3-triazole analogs and two 1,4-disubstituted 1,2,3-triazole analogs of combretastatin A-1 (1) are reported herein. The biological studies revealed that the 1,5-disubstituted 1,2,3-triazoles 3-methoxy-6-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzene-1,2-diol (6), 3-methoxy-6-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzene-1,2-diamine (8) and 5-(2,3-difluoro-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole (9) were the three most active compounds regarding inhibition of both tubulin polymerization and angiogenesis. Molecular modeling studies revealed that combretastatins 1 and 2 and analogs 5-11 could be successfully docked into the colchicine binding site of α,β-tubulin.     

Inhibitory effect on NO production of phenolic compounds from Myristica fragrans

Three new phenolics: ((7S)-8'-(benzo[3',4']dioxol-1'-yl)-7-hydroxypropyl)benzene-2,4-diol (1), ((7S)-8'-(4'-hydroxy-3'-methoxyphenyl)-7-hydroxypropyl)benzene-2,4-diol (2) and ((8R,8'S)-7-(4-hydroxy-3-methoxyphenyl)-8'-methylbutan-8-yl)-3'-methoxybenzene-4',5'-diol (3), along with four known compounds (4-7) were isolated from the seeds of Myristica fragrans. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. Their anti-inflammatory activity was evaluated against LPS-induced NO production in macrophage RAW264.7 cells.     

In vivo properties of thiol inhibitors of the three vasopeptidases NEP, ACE and ECE are improved by introduction of a 7-azatryptophan in P2' position.

Three zinc metallopeptidases are implicated in the regulation of fluid homeostasis and vascular tone and represent interesting targets for the treatment of chronic heart failure. We have previously reported the synthesis of a triple inhibitor able to simultaneously inhibit neprilysin (NEP, EC 3.4.24.11), angiotensin-converting enzyme (ACE, EC 3.4.15.1) and endothelin-converting enzyme (ECE-1, EC 3.4.24.71) with nanomolar potency towards NEP and ACE and a lesser affinity for ECE. Here, we report the optimization and biological activities of analogs derived from lead compound 1 (2S)-2-[(2R)-2-((1S)-5-bromo-indan-1-yl)-3-mercapto-propionylamino]-3- (1H-indol-3-yl)-propionic acid by a structural approach. Among several inhibitors, compound 21, (2S)-2-[(2R)-2-((1S)-5-bromo-indan-1-yl)-3-mercapto-propionylamino]-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid was selected by taking into account its good molecular adaptation with the recently published structures of the three vasopeptidases. This optimization procedure led to an improved pharmacologic activity when compared with 1.     

Synthesis of modified nucleotide building blocks containing electrophilic groups in the 2'-position

Chemical syntheses of 2'-O-(allyloxycarbonyl)methyladenosine, 2'-O-(methoxycarbonyl)methyladenosine and 2'-O-(2,3-dibenzoyloxy)propyluridine 3'-2-cyanoethyl-N,N-diisopropyl phosphoramidite building blocks are described. These monomers were used successfully to incorporate carboxylic acid, 1,2-diol and aldehyde functionalities into synthetic oligonucleotides.     

A Mechanistic Study of the Dihydroflavin Reductive Cleavage of the Dihydroflavin-Tetrahydronaphthalene Epoxide Adducts

Dihydroflavins are facile reducing agents and potent nucleophiles. The dihydroflavin nucleophilic reactivity, as measured by the rate of covalent flavin adduct formation with tetrahydronaphthalene epoxides, is comparable to that of the thiolate anion (Y. T. Lee and J. F. Fisher (1993) J. Org. Chem. 58, 3712). In these reactions there appears subsequent to the nucleophilic cleavage of the epoxide by the dihydroflavin the product corresponding to formal hydride reduction product (at the benzylic carbon) of these epoxides. Thus the reaction of (+/-)-1a,2,3, 7b-tetrahydro-(1aalpha,2alpha,3beta,7balpha)-naphth[1,2-b]oxirene-2,3-diol (1), (+/-)-1a,2,3,7b-tetrahydro-(1aalpha,2beta,3alpha,7balpha)-naphth[1,2-b]oxirene-2,3-diol (2), and (+/-)-1a,2,3,7b-tetrahydro-(1aalpha,7balpha)-naphth[1,2-b]oxirene (3) in 9:1 (v/v) aqueous Tris buffer-dioxane, at both acidic and neutral pH, with FMNH(2) and 1,5-dihydrolumiflavin (LFH(2)) gave (following covalent flavin-epoxide adduct formation) the products having a methylene group at the benzylic position. The reduction product yield was proportional to the yield of the N(5) flavin-epoxide adduct intermediate, and the rate of the reaction was proportional to the dihydroflavin concentration. These observations are consistent with these reduction products resulting from bimolecular reaction between the dihydroflavin-epoxide adduct and a second molecule of dihydroflavin. Copyright 2000 Academic Press.     

Isatin 1,2,3-triazoles as potent inhibitors against caspase-3

Sixteen disubstituted 1,2,3-triazoles were prepared using the Huisgen cycloaddition reaction and evaluated as inhibitors against caspase-3. The two most potent inhibitors were found to be (S)-1-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (7f) and (S)-1-((1-benzyl-1H-1,2,3-triazol-5-yl)methyl)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (8g) with IC₅₀-values of 17 and 9 nM, respectively. Lineweaver-Burk plots revealed that these two triazoles show competitive inhibitory mechanism against caspase-3.     

A highly convergent and effective synthesis of the phytoalexin elicitor hexasaccharide.

The peracetylated hexasaccharide 1,2,4-tri-O-acetyl-3-O-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-6- O- (2,3,4-tri-O-acetyl-6-O-(2,4-di-O-acetyl-3,6-di-O-(2,3,4,6-tetra-O-acety l- beta-D-glucopyranosyl)-beta-D-glucopyranosyl)-beta-D-glucopyranosyl)-alp ha, beta-D-glucopyranose 21 was synthesized in a blockwise manner, employing trisaccharide trichloroacetimidate 2,4-di-O-acetyl-3,6-di-O-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)- alpha-D-glucopyranosyl trichloroacetimidate 17 as the glycosyl donor, and trisaccharide 4-O-acetyl-3-O-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-6-O-(2,3,4 -tri -O-acetyl-beta-D-glucopyranosyl)-1,2-O-(R,S)ethylidene-alpha-D-glucopyra nose 18 as the acceptor. The donor 17 and acceptor 18 were readily prepared from trisaccharides 3-O-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-6-O-(2,3,4-tri-O-acet yl- 6-O-chloroacetyl-beta-D-glucopyranosyl)-1,2-O-(R,S)ethylidene-alpha-D- glucopyranose 10 and 3,6-di-O-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-1,2-O-(R,S) ethylidene-alpha-D-glucopyranose 11, respectively, which were obtained from rearrangement of orthoesters 3,4-di-O-acetyl-6-O-chloroacetyl-alpha-D-glucopyranose 1,2-(3-O-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-1,2-O-(R,S) ethylidene-alpha-D-glucopyranosid-6-yl orthoacetate) 8 and 3,4,6-tri-O-acetyl-alpha-D-glucopyranose 1,2-(3-O-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-1,2-O-(R,S) ethylidene-alpha-D-glucopyranosid-6-yl orthoacetate) 9, respectively. The orthoesters were prepared from selective coupling of the disaccharide 3-O-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-1,2-O-(R,S) ethylidene-alpha-D-glucopyranose 4 with 'acetobromoglucose' (tetra-O-acetyl-alpha-D-glucopyranosyl bromide) and 6-O-chloroacetylated 'acetobromoglucose', respectively. To confirm the selectivity of the orthoester formation and rearrangement, the disaccharide 4-O-acetyl-3-O-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-1,2-O-(R,S ) ethylidene-alpha-D-glucopyranose 7 was prepared from 4 by selective tritylation, acetylation and detritylation. The title compound, an elicitor-active D-glucohexaose 3-O-(beta-D-glucopyranosyl)-6-O-(6-O-(3,6-di-O-(beta-D-glucopyranosyl)-b eta -D-glucopyranosyl)-beta-D-glucopyranosyl)-alpha,beta-D-glucopyranose 1, was finally obtained by Zemplén deacetylation of 21 in quantitative yield.     

Dimerization of Bisphenol A by Hyper Lignin-Degrading Fungus Phanerochaete sordida YK-624 Under Ligninolytic Condition

Bisphenol A (BPA) was treated with hyper lignin-degrading fungus Phanerochaete sordida YK-624 under ligninolytic condition. After preculturing P. sordida YK-624 for 4 days, BPA (final concentration, 1 and 0.1 mM) was added to cultures. Both 1- and 0.1-mM BPA were effectively decreased within a 24-h treatment and two metabolites were detected. Two metabolites (5,5′-bis-[1-(4-hydroxy-phenyl)1-methyl-ethyl]-biphenyl-2,2′-diol and 4-(2-(4-hydroxy-phenyl) propan-2-yl)-2-(4-(2-(4-hydroxyphenyl) propan-2-yl) phenoxy)phenol) were identified by ESI–MS and NMR analysis. These results indicated that BPA was oxidized to BPA phenoxy radicals by ligninolytic enzymes and then dimerized at extracellular region.     

Rhodococcus erythropolis DCL14 contains a novel degradation pathway for limonene

Strain DCL14, which is able to grow on limonene as a sole source of carbon and energy, was isolated from a freshwater sediment sample. This organism was identified as a strain of Rhodococcus erythropolis by chemotaxonomic and genetic studies. R. erythropolis DCL14 also assimilated the terpenes limonene-1,2-epoxide, limonene-1,2-diol, carveol, carvone, and (-)-menthol, while perillyl alcohol was not utilized as a carbon and energy source. Induction tests with cells grown on limonene revealed that the oxygen consumption rates with limonene-1,2-epoxide, limonene-1,2-diol, 1-hydroxy-2-oxolimonene, and carveol were high. Limonene-induced cells of R. erythropolis DCL14 contained the following four novel enzymatic activities involved in the limonene degradation pathway of this microorganism: a flavin adenine dinucleotide- and NADH-dependent limonene 1, 2-monooxygenase activity, a cofactor-independent limonene-1, 2-epoxide hydrolase activity, a dichlorophenolindophenol-dependent limonene-1,2-diol dehydrogenase activity, and an NADPH-dependent 1-hydroxy-2-oxolimonene 1,2-monooxygenase activity. Product accumulation studies showed that (1S,2S,4R)-limonene-1,2-diol, (1S, 4R)-1-hydroxy-2-oxolimonene, and (3R)-3-isopropenyl-6-oxoheptanoate were intermediates in the (4R)-limonene degradation pathway. The opposite enantiomers [(1R,2R,4S)-limonene-1,2-diol, (1R, 4S)-1-hydroxy-2-oxolimonene, and (3S)-3-isopropenyl-6-oxoheptanoate] were found in the (4S)-limonene degradation pathway, while accumulation of (1R,2S,4S)-limonene-1,2-diol from (4S)-limonene was also observed. These results show that R. erythropolis DCL14 metabolizes both enantiomers of limonene via a novel degradation pathway that starts with epoxidation at the 1,2 double bond forming limonene-1,2-epoxide. This epoxide is subsequently converted to limonene-1,2-diol, 1-hydroxy-2-oxolimonene, and 7-hydroxy-4-isopropenyl-7-methyl-2-oxo-oxepanone. This lactone spontaneously rearranges to form 3-isopropenyl-6-oxoheptanoate. In the presence of coenzyme A and ATP this acid is converted further, and this finding, together with the high levels of isocitrate lyase activity in extracts of limonene-grown cells, suggests that further degradation takes place via the beta-oxidation pathway.     

Antitumor evaluation and molecular docking study of substituted 2-benzylidenebutane-1,3-dione, 2-hydrazonobutane-1,3-dione and trifluoromethyl-1H-pyrazole analogues

Abstract

A series of 2-(arylidene)-1-(4-chlorophenyl)-4,4,4-trifluorobutane-1,3-diones (2–4), 4-(arylidene)-3-(4-chlorophenyl)-5-(trifluoromethyl)-4H-pyrazoles (5–7), 1-(4-chlorophenyl)-4,4,4-trifluoro-2-(2-(aryl)hydrazono)butane-1,3-diones (8, 9), 3-(4-chlorophenyl)-4-(2-(aryl)hydrazono)-5-(trifluoromethyl)-4H-pyrazoles (10, 11), 2-((3-(4-chlorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methylene)malononitrile (13), 2-((5-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methylene)cycloalkan-1-ones (14, 15) and 1-(aryl)-3-(5-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)prop-2-en-1-ones (16, 17) were designed, synthesized and evaluated for their in vitro antitumor activity. 1-(4-Chlorophenyl)-4,4,4-trifluoro-2-(2-(4-methoxyphenyl)hydrazono)butane-1,3-dione (8) showed potential and broad spectrum antitumor activity compared to the known drug 5-FU with GI₅₀, (6.61 and 22.60 µM), TGI (42.66 and <100?µM) and LC₅₀ (93.33 and <100?µM) values, respectively. On the other hand, compound 8 yielded selective activities toward melanoma, colon, non-small lung and breast cancer cell lines compared with erlotinib and gefitinib. Molecular docking methodology was performed for compound 8 into binding site of B-RAFV600E and EGFR kinases which showed similar binding mode to vemurafenib (PLX4032) and erlotinib, respectively.