Methylenedioxyphenyl Research Articles

Biodegradation of the methylenedioxyphenyl group in piperine and its derivatives: discovery of a novel methylenetransferase in an actinomycete.

Pepper is a spice that has been used worldwide since the Age of Discovery. The substance that is responsible for the spiciness in pepper is piperine, a type of alkaloid. It has never been reported how piperine is degraded by microorganisms. In this study, we discovered a bacterium in the soil that is capable of catabolizing piperine as its sole nitrogen source. Furthermore, we discovered the enzyme involved in piperine metabolism. This enzyme decomposed the methylenedioxyphenyl group, which is the common structure in various plant-derived bioactive compounds such as sesamin, piperonal, safrole, and berberin. By utilizing this enzyme, piperine can be converted into a useful antioxidant compound. The findings about previously unknown metabolic pathways in nature can lead to the discovery of new enzymes and provide methods for the enzymatic synthesis of useful compounds.

Alternative co-initiators for photocurable dental resins: Polymerisation, quantum yield of conversion and cytotoxicity

ObjectiveCyclic acetals such as are naturally occurring compounds capable of acting as co-initiators during free-radical polymerisation, and potentially serve to offer non-allergic and biologically less toxic alternatives to conventional (tertiary) amines. The current study aimed to evaluate the polymerisation efficiency and potential toxicity of cyclic acetals compared with conventional photoinitiator systems in photocurable dental resins. MethodsBoth, 1,3 benzodioxole (BZD) and piperonyl alcohol (PA) were used in 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 and 6.0 mol% concentrations. Whereas, N-phenyl glycine (NPG) was utilised in 0.5, 1.0, 1.5, 2.0, 3.0, 4.0 mol% concentrations for photopolymerisation of an unfilled model resin system, BisGMA and TEGDMA (1:1 mass %), involving three separate camphorquinone (CQ) concentrations of 0.5 (Low), 1.0 (Intermediate) and 1.5 (High) mol%. Conventional tertiary amines; ethyl-4-dimethyamino benzoate (EDMAB) and dimethylaminoethyl methacrylate (DMAEMA) were utilised for comparison. Real-time degree of conversion (DC, %) was evaluated using Fourier transform near-infra-red spectroscopy and quantum yield of conversion of CQ was calculated using UV-Vis spectroscopy. Cytotoxicity of NPG and cyclic acetals were assessed using MTT to determine metabolic activity of human dental pulp cells (HDPCs). ResultsThe cyclic acetals were capable of facilitating free radical polymerisation as co-initiators at all three CQ concentrations. Furthermore, the use of NPG as a co-initiator resulted in post-irradiation DC (%) that were comparable to both EDMAB and DMAEMA for all CQ concentrations. Alternative compounds facilitated the hydrogen abstraction process, which provided high conversion of CQ molecules. Quantum yield increased from 0.009 ± 0.0001 (0.5 mol%) to 0.03 ± 0.006 (6.0 mol%), and 0.01 ± 0.0003 (0.5 mol%) to 0.04 ± 0.001 (6.0 mol%), for respective BZD and PA formulations involving 1.0 mol% CQ. The use of NPG led to relatively higher quantum yield values (Up to 0.09 ± 0.007 at 4.0 mol%), though it exhibited competitive effects in absorbing blue light, which might be attributed to the photolytic degradation of NPG and the formation of N-methylaniline. MTT assay indicated alternative co-initiators to be comparatively less cytotoxic than EDMAB and CQ. Relative metablic activity of HDPCs treated with BZD, PA, and NPG eluates were 58.3 ± 15.7, 57.5 ± 17.4 and 64.6 ± 12.2 %, when compared with untreated HDPCs group (Control), respectively. Exposure to DMAEMA-based eluate led to relative metabolic activity (60.0 ± 0.5 %) that was comparable to that of cyclic acetals. Treatment with neat model resin eluate displayed the highest relative reduction in metabolic activity (28.9 ± 22.4) (P < 0.05), suggesting bisGMA and TEGDMA monomers played significant role in the overall cytotoxicity of photocurable systems involving HDPCs. SignificanceCyclic acetals were capable of facilitating photo-induced free radical polymerisation reactions with relatively less cytotoxicity compared with their amine counterparts, which might realise reduced cytotoxicity of photocurable materials used for dentistry and biomaterial applications.

Alternative Co-Initiators for Photocurable Biomaterials: Polymerisation, Quantum Yield of Conversion and Cytotoxicity

Cyclic acetals such as 1,3 benzodioxole (BZD), piperonyl alcohol (PA), and N-phenyl glycine (NPG) are naturally occurring compounds capable of acting as co-initiators during free-radical polymerisation, and potentially serve to offer non-allergic and biologically less toxic alternatives to conventional (tertiary) amines. The current study aimed to evaluate the use of cyclic acetals in concentrations of 0.5-6.0 mol % for photopolymerisation of an unfilled model dimethacrylate resin system, bisphenol-A-glycidyldimethacrylate (BisGMA), and triethylene glycol dimethacrylate (tegDMA), 1:1 wt.%) using the photosensitiser camphorquinone (CQ; λmax = 469 nm) in concentrations of 0.5-1.5 mol %. Conventional tertiary amines, namely, ethyl-4-dimethyamino benzoate (EDMAB) (aromatic) and dimethylaminoethyl methacrylate (DMAEMA) (aliphatic) were utilised for comparison purposes. Real-time degree of conversion (DC) was evaluated using Fourier transform near-infrared spectroscopy. To measure the effectiveness of these alternative compounds in facilitating CQ photon absorption, quantum yield of conversion of CQ per absorbed photon was calculated using UV-Vis spectroscopy. Cytotoxicity of NPG and cyclic acetals were assessed using MTT and Calcien AM to determine metabolic activity and cell viability, respectively. The result indicated that cyclic acetals were capable of facilitating free radical polymerisation as co-initiators at all three CQ concentrations (0.5, 1.0 and 1.5 mol %). Further, the use of NPG as a co-initiator resulted in post-irradiation DC values that were comparable to both EDMAB and DMAEMA across all three CQ concentrations. Based on the quantum yield of conversion of CQ, alternative compounds facilitated the hydrogen abstraction process, which provided high conversion of CQ molecules. UV-Vis absorption and quantum yield data revealed that NPG exhibited competitive effects in absorbing blue light photons, which might be attributed to the photolytic degradation of NPG and the formation of N-methylaniline. Indirect treatment of human dental pulp cells (HDPCs) with eluted extracts of NPG, BZD and PA exhibited relatively lower cytotoxicity when compared with HDPCs groups treated with no eluted extracts. The relative cytotoxicity of DMAEMA was comparable to that of PA. However EDMAB, CQ and the neat model resin media extracts resulted in significant cytotoxicity, with highest relative reduction in the number of viable cells observed in groups treated with neat model resin extracts, suggesting that bisGMA and tegDMA monomers played significant role in the overall cytotoxicity of photocurable systems involving HDPCs.

Chemical constituents from the leaves of Cinnamomum camphora var. linaloolifera and their anti-inflammatory activities

Thirteen compounds were isolated and purified from the leaves of Cinnamomum camphora by the macroporous resin,silica gel,and Sephadex LH-20 column chromatographies. Those compounds were further identified by IR,UV,MS,and NMR techniques:( 2 S)-1-( 3″,4″-methylenedioxy phenyl)-3-( 2&apos;,6&apos;-dimethoxy-4&apos;-hydroxyphenyl)-propan-2-ol( 1),( 2 R,3 R)-5,7-dimethoxy-3&apos;,4&apos;-methylenedioxy flavanol( 2),9-hydroxysesamin( 3),sesamin( 4),piperitol( 5),kobusin( 6),(-)-aptosimon( 7),acuminatolide( 8),1β,11-dihydroxy-5-eudesmene( 9),lasiodiplodin( 10),vanillin( 11),p-hydroxybenzaldehyde( 12),and p-hydroxybenzoic acid ethyl ester( 13). Compound 1 was a novel compound,and compounds 2,6,7,9 and 10 were isolated from Cinnamomum plants for the first time. Compounds 4,7 and 10 were found to possess good inhibitory effect on IL-6 production in LPS-induced BV2 cells at a concentration of 20 μmol·L-1 in the in vitro bioassay,with inhibition rates of 51. 26% ± 4. 13%,67. 82% ± 3. 77% and85. 81%±1. 19%,respectively.

Screening of Plant Extracts Possessing Methylenedioxyphenyl (MDP) Group as Potential Synergists in Insecticide Formulations using the Maize Weevil, Sitophilus Zea-mais (Motsch.)

Screening of Plant Extracts Possessing Methylenedioxyphenyl (MDP) Group as Potential Synergists in Insecticide Formulations using the Maize Weevil, Sitophilus Zea-mais (Motsch.)

Characterization of stable and reactive metabolites of piperine formed on incubation with human liver microsomes.

Black pepper, though commonly employed as a spice, has many medicinal properties. It consists of volatile oils, alkaloids, pungent resins, etc., of which piperine is a major constituent. Though safe at low doses, piperine causes alteration in the activity of drug metabolising enzymes and transporters at high dose and is known to precipitate liver toxicity. It has a potential to form reactive metabolite(s) (RM) owing to the presence of structural alerts, such as methylenedioxyphenyl (MDP), α, β-unsaturated carbonyl group (Michael acceptor), and piperidine. The present study was designed to detect and characterize stable and RM(s) of piperine formed on in vitro incubation with human liver microsomes. The investigation of RMs was done with the aid of trapping agents, viz, glutathione (GSH) and N-acetylcysteine (NAC). The samples were analysed by ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC-HRMS) using Thermo Scientific Q Exactive Plus Orbitrap. Full scan MS followed by data-dependent MS2 (Full MS-ddMS2 ) mode was used to establish mass spectrometric fragmentation pathways of protonated piperine and its metabolites. In total, four stable metabolites and their isomers (M1a-c, M2a-b, M3a-c, and M4a-b) were detected. Their formation involved removal of carbon (3, M1a-c), hydroxylation (2, M2a-b), hydroxylation with hydrogenation (3, M3a-c), and dehydrogenation (2, M4a-b). Out of these metabolites, M1, M2, and M3 are reported earlier in the literature, but their isomers and two M4 variants are novel. In addition, six novel conjugates of RMs, including three GSH conjugates of m/z 579 and three NAC conjugates of m/z 435, were also observed.

Flavone/Tertiary Amine as Free Radical Photoinitiator for UV Photopolymerization of Tripropylene Glycol Diacrylate(TPGDA)†

The polymerization kinetics of tripropylene glycol diacrylate(TPGDA) was monitored by real time near infrared(RTIR) with favone(FL) as photosensitizer and different hydrogen donor as coinitiator.The commercial photosensitizer benzophenone(BP) was used as control.The results showed that the molar extinction coefficient(e max) of FL was much higher than that of BP.When FL was used in combination with tertiary amine hydrogen donor ethyl 4-N,N'-dimethylaminobenzoate(EDAB),the rate of polymerization(R p) and final double bond conversion(DC f) could reach 0.58 s-1and 97%,respectively,which was very close to that of commercial BP / EDAB system.However,using sesamin(SM) and benzodioxole(BDO) as coinitiator for FL,the R p and DC f were both very low,which indicated that the excited FL and tertiary amine could generate aminoalkyl free radical species via electron / proton transfer process and initiate the efficient photopolymerization of TPGDA.More importantly,when the co-polymerizable tertiary amines such as EBERYL P115 and dimethylaminoethyl methacrylate(DMEM) are used,the natural component characteristics of FL make it a promising photoinitiator in biomedical and food-packaging fields.

Characterization of the Dissolution Behavior of Piperine/Cyclodextrins Inclusion Complexes.

In this study, the physicochemical properties and solubility of inclusion complexes of ground mixtures (GMs) of piperine (PP), a pungent ingredient of pepper, with α- and γ-cyclodextrin (CD) were studied. From the solubility results, the PP/αCD inclusion molar ratio was determined to be 1/2, while that of PP/γCD was 1/1, according to the AP-type phase diagram of PP/αCD and the BS-type one of PP/γCD. The powder X-ray diffraction and differential scanning calorimetry analyses confirmed the formation of GM complexes with molar ratios of PP/αCD=1/2 and PP/γCD=1/1. The Raman analysis revealed the disappearance of the bands corresponding to the C=C, O-CH2-O, -CH, and aliphatic C=C moieties of the methylene dioxyphenyl fragment of PP in the spectra of the inclusion complexes. In the dissolution tests, GM (PP/αCD=1/2) and GM (PP/γCD=1/1) showed higher solubility than free PP and the analogous physical mixtures. Furthermore, after 60min, GM (PP/αCD=1/2) exhibited higher solubility than GM (PP/γCD=1/1). In the 1H-1H nuclear Overhauser effect spectroscopy measurements, GM (PP/αCD=1/2) was found to present a head-to-head inclusion structure via the aliphatic C=C and methylene dioxyphenyl groups of PP and the two αCD molecules. In contrast, it was confirmed that γCD interacts with the O-CH2-O functionality of the methylene dioxyphenyl group of PP in a molar ratio of 1/1. It was thus concluded that the differences in the PP/CD structures influence the solubility of the inclusion complexes.

Biochemical evaluation of interactions between synergistic molecules and phase I enzymes involved in insecticide resistance in B- and Q-type Bemisia tabaci (Hemiptera: Aleyrodidae).

Metabolic resistance is an important consideration in the whitefly Bemisia tabaci, where an esterase-based mechanism has been attributed to pyrethroid resistance and over-expression of the cytochrome P450, CYP6CM1, has been correlated to resistance to imidacloprid and other neonicotinoids. In vitro interactions between putative synergists and CYP6CM1, B and Q-type esterases were investigated, and structure-activity relationship analyses allowed the identification of chemical structures capable of acting as inhibitors of esterase and oxidase activities. Specifically, methylenedioxyphenyl (MDP) moieties with a polyether chain were preferable for optimum inhibition of B-type esterase, whilst corresponding dihydrobenzofuran structures were potent for the Q-esterase variation. Potent inhibition of CYP6CM1 resulted from structures which contained an alkynyl chain with a terminal methyl group. Synergist candidates could be considered for field control of B. tabaci, especially to abrogate neonicotinoid resistance. © 2017 Society of Chemical Industry.

Synthesis and photopolymerization kinetics of 2-phenyl-benzodioxole

In this paper, a new photocoinitiator for free radical photopolymerization, belonging to the benzodioxole (BDO) derivatives, was synthesized and characterized, and the effect of phenyl at the 2-position of BDO was estimated. The structure of PhBDO was characterized by elemental analysis, (1)H NMR and (13)C NMR. Laser flash photolysis (LFP) and an electron spin resonance spin trapping technique (ESR-ST) were used to study the photochemical mechanisms. The rate of decomposition (Rd) of PhBDO in acetonitrile was studied by UV-Vis spectroscopy and the photopolymerization kinetics were monitored by real time Fourier Transform near-IR (FT-IR). The FT-IR results showed that the concentration of PhBDO and BP functionalities of the acrylates and the light intensity affected the polymerization rate and the final conversion. The results showed that the BP/PhBDO system had the same hydrogen abstraction mechanism and reactivity as the BP/BDO system. Consequently, PhBDO could also be an effective coinitiator.

Carbene Generation by Cytochromes and Electronic Structure of Heme-Iron-Porphyrin-Carbene Complex: A Quantum Chemical Study

Carbene-heme-iron-porphyrin complexes generated from cytochrome P450 (CYP450)-mediated metabolism of compounds containing methylenedioxyphenyl (MDP) moiety lead to the mechanism-based inhibition (MBI) of CYPs. This coordination complex is termed as the metabolic-intermediate complex (MIC). The bioinorganic chemistry of MDP carbenes has been studied using quantum chemical methods employing density functional theory (B3LYP functional with implicit solvent corrections) to (i) analyze the characteristics of MDP-carbene in terms of singlet-triplet energy difference, protonation, and dimerization energies, etc.; (ii) determine the electronic structure and analyze the Fe-carbene interactions; and (iii) elucidate the potential reaction pathways for the generation of carbene, using Cpd I (iron(IV)-oxo-porphine with SH(-) as the axial ligand) as the model oxidant to mimic the activity of CYP450. The results show that MDP-carbenes are sufficiently stable and nucleophilic, leading to the formation of stable MIC (-40.35 kcal/mol) on the doublet spin state, formed via interaction between σ(LP) of carbene and empty dz(2) orbital of heme-iron. This was aided by the back-bonding between filled d(xz) orbital of heme-iron and the empty p orbital of carbene. The mechanistic pathway proposed in the literature for the generation of MDP-carbene (CH hydroxylation followed by water elimination) was studied, and observed to be unfavorable, owing to the formation of highly stable hydroxylated product (-57.12 kcal/mol). An intriguing pathway involving hydride ion abstraction and proton transfer followed by water elimination step was observed to be the most probable pathway.

Toxicological Actions of Plant-Derived and Anthropogenic Methylenedioxyphenyl-Substituted Chemicals in Mammals and Insects

The methylenedioxyphenyl (MDP) substituent is a structural feature present in many plant chemicals that deter foraging by predatory insects and herbivores. With increasing use of herbal extracts in alternative medicine, human exposure to MDP-derived plant chemicals may also be significant. Early studies found that most MDP agents themselves possess relatively low intrinsic toxicity, but strongly influence the actions of other xenobiotics in mammals and insects by modulating cytochrome P-450 (CYP)-dependent biotransformation. Thus, after exposure to MDP chemicals an initial phase of CYP inhibition is followed by a sustained phase of CYP induction. In insects CYP inhibition by MDP agents underlies their use as pesticide synergists, but analogous inhibition of mammalian CYP impairs the clearance of drugs and foreign compounds. Conversely, induction of mammalian CYP by MDP agents increases xenobiotic oxidation capacity. Exposure of insects to MDP-containing synergists in the environment, in the absence of coadministered pesticides, may also enhance xenobiotic detoxication. Finally, although most MDP agents are well tolerated, several, typified by safrole, aristolochic acid, and MDP-kavalactones, are associated with significant toxicities, including the risk of hepatotoxicity or tumorigenesis. Thus, the presence of MDP-substituted chemicals in the environment may produce a range of direct and indirect toxicities in target and nontarget species.

CYP2C19 Progress Curve Analysis and Mechanism-Based Inactivation by Three Methylenedioxyphenyl Compounds

Several in vitro criteria were used to assess whether three methylenedioxyphenyl (MDP) compounds, the isoquinoline alkaloids bulbocapnine, canadine, and protopine, are mechanism-based inactivators of CYP2C19. The recently reported fluorometric CYP2C19 progress curve analysis approach was applied first to determine whether these alkaloids demonstrate time-dependent inhibition. In this experiment, bulbocapnine, canadine, and protopine displayed time dependence and saturation in their inactivation kinetics with K(I) and k(inact) values of 72.4 ± 14.7 μM and 0.38 ± 0.036 min(-1), 2.1 ± 0.63 μM and 0.18 ± 0.015 min(-1), and 7.1 ± 2.3 μM and 0.24 ± 0.021 min(-1), respectively. Additional studies were performed to determine whether other specific criteria for mechanism-based inactivation were fulfilled: NADPH dependence, irreversibility, and involvement of a catalytic step in the enzyme inactivation. CYP2C19 activity was not significantly restored by dialysis when it had been inactivated by the alkaloids in the presence of a NADPH-regenerating system, and a metabolic-intermediate complex-associated increase in absorbance at approximately 455 nm was observed. In conclusion, the CYP2C19 progress curve analysis method revealed time-dependent inhibition by these alkaloids, and additional experiments confirmed its quasi-irreversible nature. This study revealed that the CYP2C19 progress curve analysis method is useful for identifying novel mechanism-based inactivators and yields a wealth of information in one run. The alkaloids bulbocapnine, canadine, and protopine, present in herbal medicines, are new mechanism-based inactivators and the first MDP compounds exhibiting quasi-irreversible inactivation of CYP2C19.

Metabolism of myristicin by Depressaria pastinacella CYP6AB3v2 and inhibition by its metabolite

Although methylenedioxyphenyl (MDP) compounds, such as myristicin, are useful in the management of insecticide-resistant insects, the molecular mechanisms for their action in mammals and insects have not been elucidated. In this study, GC–MS analyses of methanol extracts of foliage of wild parsnip ( Pastinaca sativa) have identified myristicin as a substrate for CYP6AB3v2, an imperatorin-metabolizing cytochrome P450 monooxygenase from Depressaria pastinacella (parsnip webworm). In contrast with its strong inhibitory effects on many mammalian P450s, myristicin is effectively metabolized by CYP6AB3v2 ( V max and K m of 97.9 pmol/min/pmol P450 and 17.9 μM, respectively) at a rate exceeding that recorded previously for imperatorin, the only other known substrate for this highly specialized enzyme. The myristicin metabolite of CYP6AB3v2 is 1-(3′,4′-methylenedioxy-5′-methoxyphenyl)-2,3-epoxypropane. Molecular dockings have indicated that, unlike other epoxide metabolites of furanocoumarins, this epoxide metabolite is likely to remain in the CYP6AB3v2 catalytic site due to its low binding energy (−31.0 kcal/mol). Inhibition assays indicate that myristicin acts as a mixed inhibitor of this insect P450 and suggest that the epoxide metabolite may be an intermediate involved in the formation of P450–methylenedioxyphenyl complexes.

Benzodioxole derivative as coinitiator for dental resin

Objective. The aim of this work was to examine whether it was possible to substitute benzodioxole derivatives for amine as coinitiators for dental application. Material and Methods. A mixture of urethane dimethacrylate (UDMA)/triethylene glycol dimethacrylate (TEGDMA) (70/30 wt%), camphorquinone (CQ) and coinitiators was photocured. Real time Fourier Transform Infrared Spectroscopy with a horizontal sample holder was used to monitor the extent of polymerization. Dynamic mechanical analysis was performed over a temperature range from −50°C to 200oC, with a ramping rate of 5oC per minute, using extension mode. Results. Benzodioxole derivatives as coinitiator improved the rate of polymerization and final double bond conversion of the dental resin. The cured samples showed similar properties, e.g. modulus, glass transition temperature, water sorption and solubility. Conclusion. The results indicate that two benzodioxole derivatives, piperonyl alcohol (PAL) and benzodioxole (BDO), are viable alternatives to conventional amines as coinitiator. The biocompatibility of benzodioxole derivatives makes them more promising than amine in dental resin formulations.

Altered CYP Expression and Function in Response to Dietary Factors: Potential Roles in Disease Pathogenesis

Increasing evidence implicates dietary factors in the progression of diseases, including certain cancers, diabetes and obesity. Diet also regulates the expression and function of CYP genes, which impacts on drug elimination and may also significantly affect disease pathogenesis. Upregulation of CYPs 2E1 and 4A occurs after feeding of experimental diets that are high in fats or carbohydrates; these diets also promote hepatic lipid infiltration, which is a component of the metabolic syndrome that characterises obesity. Increased availability of lipid substrates for CYPs can enhance free radical production and exacerbate tissue injury. Similar processes may also occur in other models of experimental disease states that exhibit a component of altered nutrient utilization. Food-derived chemicals, including constituents of cruciferous vegetables and fruits, modulate CYP expression and the expression of genes that encode cytoprotective phase II enzymes. Certain dietary indoles and flavonoids activate CYP1A expression either by direct ligand interaction with the aryl hydrocarbon receptor (AhR) or by augmenting the interaction of the AhR with xenobiotic response elements in CYP1A1 and other target genes. Other dietary chemicals, including methylenedioxyphenyl (MDP) compounds and isothiocyanates also modulate CYP gene expression. Apart from altered CYP regulation, a number of dietary agents also inhibit CYP enzyme activity, leading to pharmacokinetic interactions with coadministered drugs. A well described example is that of grapefruit juice, which contains psoralens and possibly other chemicals, that inactivate intestinal CYP3A4. Decreased presystemic oxidation by this CYP increases the systemic bioavailability of drug substrates and the likelihood of drug toxicity. Dietary interactions may complicate drug therapy but inhibition of certain CYP reactions may also protect the individual against toxic metabolites and free radicals generated by CYPs. Chemicals in teas and cruciferous vegetables may also inhibit human CYP enzymes that have been implicated in the bioactivation of chemical carcinogens. Thus, food constituents modulate CYP expression and function by a range of mechanisms, with the potential for both deleterious and beneficial outcomes.

1,3-Dipolar cycloadditions of nitrones derived from protocatechuric aldehyde methylene ether : synthesis of isoxazole-4,6-diones

A series of cycloadducts, identified as csi-2,5-diaryl-3-(3',4'-methylenedioxy phenyl)-4H,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione 3 have been prepared by cycloaddition of nitrone 2 with variously substituted maleimides. All the cycloadducts are characterised by various spectral studies. The nitrones have been prepared from protocatechuric aldehyde methylene ether 1.

Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation.

Cytochrome P450 (CYP) enzymes catalyse the oxidative conversion of drugs and other lipophilic compounds to hydrophilic metabolites. Thus, CYPs play a dominant role in the elimination of drugs from the body. Inhibitory interactions occur when drugs compete for oxidation by specific CYPs whereas certain drugs increase the capacity for oxidative biotransformation by inducing the synthesis of new CYPs. Methylenedioxyphenyl (MDP) compounds have been widely employed as commercially important pesticide synergists and a number of derivatives are found in oils and spices. MDP compounds are of considerable toxicological significance because of their capacity to inhibit and induce CYP enzymes in mammals; some derivatives produce neurotoxic and hepatotoxic effects. Although there are relatively few therapeutic agents of present clinical importance that possess the MDP structural feature, the synthesis and preclinical evaluation of such agents appears to be increasing. In the context of the existing literature surrounding MDP compounds it is noteworthy that these potential drugs also elicit significant modulatory effects on CYP activities in rat and human liver. These developments indicate the importance of understanding the chemical mechanisms by which MDPs interact with CYPs. Thus, the presence of the MDP structure may undermine the potential clinical value of new drugs.

Ring Closure Reactions of Chalcones Using Microwave Technology

The synthesis of heterocyclic compounds containing pyrimidine, pyrazoline, isoxazoline and cyclohexenone ring from chalcone derivatives containing anisole and 3′4′-methylenedioxy phenyl ring under ‘dry conditions’ using microwaves and by conventional methods are described.

Regulation of cytochrome P-450 isozymes CYP1A1, CYP1A2 and CYP2B10 by three benzodioxole compounds

Three benzodioxole (BD) compounds were used to investigate the structural requirement for regulation of the cytochrome P450 isozymes, CYP1Al, CYP1A2 and CYP2B10, in mouse liver. Male mice (C57BL/6) were treated intraperitoneally for 3 days with 5- t-butyl-1,3-benzodioxole (t-BBD), 5- n-butyl-1,3-benzodioxole (n-BBD) and 5-(3-oxobutyl)-1,3-benzodioxole (o-BBD). t-BBD-induced liver microsomes showed the highest pentoxyresorufin O-dealkylation (PROD) activity, while o-BBD induced microsomes showed slightly higher activity in ethoxyresorufin O-deethylation (EROD), benzo[ a]pyrene hydroxylation (BaP-OH) and acetanilide hydroxylation (Acet-OH) assays. In vitro enzyme inhibition assays showed that n-BBD inhibited EROD and Acet-OH activities more than either o-BBD or t-BBD, while PROD activity was evenly inhibited by all three compounds. Western and northern blots showed that CYP1A1 was not detectably induced by any of the three BD compounds. The levels of CYP1A2 protein and mRNA were increased in all three treated livers. In addition to CYP1A2 induction, t-BBD also induced the protein and mRNA for CYP2B10.