Generation of hydroxyl radicals by the intramolecular oxidation of tricyclic artemisinin analogs and their antimalarial activity

The kinetic schemes were constructed for the intramolecular oxidation of four tricyclic artemisinin derivatives differed in number and arrangement of the methyl groups. Each step of the scheme was characterized by the enthalpy. The activation energies and rate constants were calculated by using the intersecting parabolas model. Three of the four tricyclic derivatives were found to undergo intramolecular oxidation, and the hydroperoxide groups formed generate free radicals. Owing to this, the compounds possess antimalarial activity. The fourth compound is not substantially oxidized due to certain specific features of its structure and exhibits no antimalarial activity. The latter correlates with the number of hydroxyl radicals generated by the compound (n _OH). The dep endence of the IC₅₀ index on n _OH is nonlinear. Three elementary reactions leading to the generation of reactive hydroxyl radicals were identified.     

Hydroxyl mechanism of the antimalarial action of dimeric analogues of artemisinin

Kinetic schemes of intramolecular oxidation have been constructed for four model compounds containing two artemisinin residues. Each step of the kinetic scheme has been characterized by an enthalpy of reaction. The activation energy and rate constant have been calculated using the intersecting-parabolas model. The competition between unimolecular and bimolecular reactions has been taken into account in constructing the kinetic scheme. In the case of H atom abstraction from the C-H bond in the α-position with respect to the hydroperoxyl group, the fragmentation of the molecule concerted with H abstraction has been taken into consideration. The intramolecular oxidation of the model compounds yields hydroperoxide groups, which, reacting with Fe(II), generate free radicals. Among the latter, hydroxyl radicals play the key role, as in the case of artemisinin. It is the number of hydroxyl radicals generated by the artemisinin analogues (n _OH) that correlates with their antimalarial activity. The relationship between the effectiveness of the dimeric analogues, which is characterized by IC ₅₀, and n _OH is linear and, in the n _OH = 3–7 range, is given by the formula IC ₅₀(artemisinin)/IC ₅₀(analogue) = 1 + 0.27/(n _OH ? 3.17).     

Free-radical generation mechanism and antimalarial activity of cyclohexyl endoperoxides

A kinetic analysis has been carried out for a cascade of intramolecular oxidation reactions of free radicals generated in the redox reactions of substituted cyclohexyl endoperoxides (15 compounds) with the Fe²⁺ ion. Each radical conversion reaction has been characterized by its enthalpy, activation energy, and rate constant. Kinetic characteristics have been calculated by the intersecting parabolas method. Depending on their structure, cyclohexyl endoperoxides generate one to three radicals. There is a linear empirical correlation between the number of radicals generated by a peroxide and its molar antimalarial activity (IC ₅₀/M, where M is the molar mass of the peroxide). The peroxides that generate no more than one radical show no antimalarial activity.     

An important role of intramolecular free radical reactions in antimalarial activity of artemisinin and its analogs

The kinetic schemes of intramolecular reactions of five analogs of artemisinin were built. The method of intersecting parabolas was used for the calculation of activation energies and rate constants of each elementary step of these schemes. The competition between monomolecular and bimolecular free radicals was taken into account. It was evidenced that the intramolecular oxidation of these compounds proceeds as a cascade of consecutive free radical reactions with the formation of hydroperoxide groups. The latter decompose via reactions with the Fe(II) complexes generating free radicals. Among the radicals formed, the hydroxyl radical was proved to play the key role. A correlation between the yield of hydroxyl radicals n(OH) and antimalarial activity of compounds (IC(50)) was observed. The dependence of index IC(50) on n(OH) is linear in the logarithmic coordinates: ln[IC(50)(Artemisinin)/IC(50)(Compound)] = -14.10 + 3.85 ×n(OH). The proposed scheme explains and demonstrates a strong dependence of the antimalarial effectiveness of a drug on the chemical structure.     

A DFT study of proton transfers for the reaction of phenol and hydroxyl radical leading to dihydroxybenzene and H2O in the water cluster

Reactions of phenol and hydroxyl radical were studied under the aqueous environment to investigate the antioxidant characters of phenolic compounds. M06‐2X/6‐311 + G(d,p) calculations were carried out, where proton transfers via water molecules were examined carefully. Stepwise paths from phenol + OH^• + (H₂O)_n (n = 3, 7, and 12) to the phenoxyl radical (Ph O^•) via dihydroxycyclohexadienyl radicals (ipso, ortho, meta, and para OH‐adducts) were obtained. In those paths, the water dimer was computed to participate in the bond interchange along hydrogen bonds. The concerted path corresponding to the hydrogen atom transfer (HAT, apparently Ph OH + OH^• → Ph O^• + H₂O) was found. In the path, the hydroxyl radical located on the ipso carbon undergoes the charge transfer to prompt the proton (not hydrogen) transfer. While the present new mechanism is similar to the sequential proton loss electron transfer (SPLET) one, the former is of the concerted character. Tautomerization reactions of ortho or para (OH)C₆H₅=O + (H₂O)_n → C₆H₄(OH)₂(H₂O)_n were traced with n = 2, 3, 4, and 14. The n = 3 (and n = 14) model of ortho and para was calculated to be most likely by the strain‐less hydrogen‐bond circuit.     

Generation of radicals and antimalarial activity of dispiro-1,2,4-trioxolanes

The kinetic schemes of the intramolecular oxidation of radicals generated from substituted dispiro-1,2,4-trioxolanes (seven compounds) in the presence of Fe²⁺ and oxygen were built. Each radical reaction was defined in terms of enthalpy, activation energy, and rate constant. The kinetic characteristics were calculated by the intersecting parabolas method. The competition between the radical reactions was considered. The entry of radicals generated by each compound into the volume was calculated. High antimalarial activity was found for 1,2,4-trioxolanes, which generated hydroxyl radicals. The structural features of trioxolanes responsible for the generation of hydroxyl radicals were determined.     

C?H bond dissociation enthalpies of fluorinated formates and estimation of their rate constants for the reactions with OH radicals: A DFT study

Density functional theory was used to estimate the lifetime of fluorinated formates, which are primary products from the oxidation of hydrofluoroethers. First, the C? H bond dissociation enthalpies (BDEs) of 10 fluorinated formates, C_nF_{2n + 1}OC(O)H (n = 1–4) and C_nHF_2nOC(O)H (n = 1–3) have been calculated by using the density functional theory with (RO)B3LYP/6‐311G(d,p). Secondly, from these computed BDEs, the rate constants k_OH of the hydrogen abstraction reaction between the fluorinated formates and OH radicals have been estimated using the formulation proposed by Heicklen (Int. J. Chem. Kinet. 13 , 651, 1981). We modified the formulation proposed by Heicklen in order to relate BDEs to k_OH for formates based on the results of the ab initio studies using standard transition state theory with the G2(MP2) level. Consequently, the k_OH of all the formates considered here are estimated to be around 1.5–4.7 × 10^?14 cm³ molecule^?1 s^?1 at 298 K. Their lifetimes concerning with the decomposition by OH radicals (τ_OH) in atmosphere have been evaluated as 0.4–4.5 years from the estimated k_OH. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 34: 524–530, 2002     

Reactions of mono- and bimolecular hydrogen transfer in alkyl radicals: analysis using the parabolic model and density functional calculations

Experimental data on monomolecular hydrogen transfer in the reactions of the type RC^·H(CH₂)_nCH₂R¹ RCH₂(CH₂)_nC^·HR¹ (n = 2—4, R and R¹ are alkyl substituents) were analyzed using the parabolic model (PM). The parameters characterizing this class of reactions were calculated. Isomerization of alkyl radicals via cyclic transition states (TS) is characterized by the following energy barriers to thermoneutral reaction E _e0: 53.5, 65.4, and 63.2 kJ mol^–1 for the six-, five-, and seven-membered TS, respectively. The E _e0 energy and the strain energy change in parallel in the series of cycloparaffins C_nH_2n. Density functional calculations of intramolecular hydrogen transfer in the n-butyl and n-pentyl radicals and of the bimolecular hydrogen abstraction from the ethane molecule by the ethyl radical were performed. The activation energies of the intra- and intermolecular hydrogen transfer were compared. The parameters of the PM were compared with the interatomic distances in the reaction center of the TS calculated by the density functional method.     

Model studies on the active site of carbonic anhydrase: Ligand properties and CO2 binding

In view of building a workable molecular model of tetraliganded zinc at the active site of carbonic anhydrase, an ab initio SCF study using pseudopotentials is performed on Zn²⁺(OH₂)_n from n = 2 to 6, Zn²⁺(NH₃)_n?1 (OH₂) for n = 2 and 4, Zn²⁺(NH₃)₂ (imidazole) (OH₂), and their ionized species involving OH^? or imidazolate, considering in particular the evolution of the properties of the ligands and of the bound cation upon increasing n and upon replacement of one ligand by another. (Comparison of NH₃ and imidazole binding was made in a full SCF calculation.) The results obtained in the tetraliganded complex confirm that zinc binding facilitates water deprotonation more than imidazole deprotonation, so as to reverse the order of their intrinsic ease of ionization. A study of the approach of CO₂ toward the active site is made in an electrostatic approximation using as models the most representative of the computed four-ligand complexes.     

Antioxidant,antimicrobial, and tyrosinase inhibition activities of acetone extract of <Emphasis Type="Italic">Ascophyllum nodosum</Emphasis>

The search for new antioxidants of natural origin derived from plants and seaweeds is still very important at present. In our study, the acetone extract of A. nodosum was investigated for its potential use as a natural antioxidant, natural feed additive with antibacterial activity and as a tyrosinase inhibitor. This study could be useful in the context of improved utilization of the A. nodosum extract in the food and cosmetics industry, being not only economically advantageous but also environmentally friendly. Extracts showed antioxidant activity with application of different methodologies: 1,1-diphenyl-2-picrilhydracil DPPH· radicals scavenging (39 %, 4 mg of freeze-dried sample), β-carotene-linoleic acid antioxidant assay (11 %, 4 mg of freeze-dried sample), O₂· radicals scavenging activity (IC₅₀ 0.43 mg mL⁻¹), OH· radicals scavenging activity (IC₅₀ 1.55 mg mL⁻¹), and iron chelation ability (IC₅₀ 0.56 mg mL⁻¹). The extract showed considerable antibacterial activity being more effective against gram-positive bacteria (Micrococcus luteus, Staphylococcus aureus) than against gram-negative bacteria (Escherichia coli, Enterococcus aerogenes). Results of tyrosinase assay for the acetone extract of Ascophyllum nodosum presented 65.6 % inhibition of tyrosinase activity at the IC₅₀ value of 0.1 mg mL⁻¹. The outcomes of our study support potential utilization of this brown seaweed as a source of natural antioxidants. Antioxidant activity of the studied seaweed can be apparently explained by the free radicals scavenging activity, particularly related to the mechanisms of O₂⁻· radicals scavenging activity, OH· radicals inactivation, and iron chelation ability.     

Outer‐sphere reduction of hexacyanoferrate(III) by enolizable and nonenolizable aldehydes in alkaline medium

Outer‐sphere reduction of hexacyanoferrate(III) by some enolizable/nonenolizable aldehydes (viz., aliphatic, heterocyclic, and aromatic aldehydes) in alkaline medium has been studied spectrophotometrically at λ_max = 420 nm. The reactions are first order each in [aldehyde] and [Fe(CN)₆^3?]. The rate increases with an increase in [OH^?] in the oxidation of aliphatic and heterocyclic aldehydes, whereas it is independent of [OH^?] in the reaction with aromatic aldehydes. The intervention of free radicals in the reaction mixture was carried out using both acrylonitrile and acrylamide scavenger in two different experiments. The kinetic results indicate that the oxidation of benzaldehyde in aqueous medium proceeds at a slower rate than the aliphatic aldehydes (other than formaldehyde) and furfural. The values of third‐order rate constant (k₃) at 308 K in the oxidations of some aliphatic aldehydes and furfural follow the order (CH₃)₂CH? > CH₃CH₂? > CH₃? > C₄H₃O? > H? . The rate constants correlate with Taft's σ* value, the reaction constant being negative (–9.8). The pseudo–first‐order rate constants in the oxidations of benzaldehyde and substituted benzaldehydes follow the order ? NO₂ > ? H > ? Cl > ? OCH₃. The Hammett plot is also linear with a ρ value (0.6488) for meta‐ and para‐substituted benzaldehydes. The kinetic isotope effect for benzaldehyde (k_H/k_D = 1.93 at 303 K) was obtained. The rate‐determining step is the outer‐sphere formation of Fe(CN)₆^4? and free radicals, which is followed by the rapid oxidation of free radicals by Fe(CN)₆^3? to give products. The kinetic data and hence thermodynamic parameters have been used to distinguish enolizable and nonenolizable aldehydes. An attempt has also been made to correlate kinetic data with hydration equilibrium constants of some aliphatic aldehydes. © 2012 Wiley Periodicals, Inc. Int J Chem Kinet 44: 494–505, 2012     

聚合Al13晶体的制备及表征

近几十年来 , 环境污染的日益严重使人们对健康问题和全球生态系统越来越关注 ?由于一个元素的生物可给性在很大程度上取决于它存在的物理化学形态和浓度 , 准确测定环境和生物体系中的痕量元素的不同形态是研究这些元素的生物毒性 ? 生物有效性和传输机理的关键 ?形态分析成了     

Production of O2- in photolyzed water demonstrated through the use of superoxide dismutase

Abstract— The photolysis of water has been studied using ferricytochrome c as the detector of reducing radicals and ferrocytochrome c as the detector of oxidizing radicals. Mannitol was used as a scavenger of hydroxyl radicals and superoxide dismutase was used to expose the specific involvement of superoxide radicals. Aerobic photolysis caused a reduction of ferricytochrome c, which was inhibited by superoxide dismutase and was enhanced by mannitol. Aerobic photolysis also caused the oxidation of ferrocytochrome c, which was inhibited by mannitol and augmented by superoxide dismutase. The presence of superoxide dismutase also eliminated the effects of mannitol on the aerobic oxidation of ferrocytochrome c. Photolysis in the absence of oxygen also caused the reduction of ferricytochrome c and the oxidation of ferrocytochrome c, but under these anaerobic conditions neither mannitol nor superoxide dismutase exerted significant effects. An explanation of these observations is offered in terms of the reactivities of H^., OH^. and O^-2 radicals.     

Reactive intermediates during oxindation of water lead dioxide and platinum electrodes

Experiments on the interception of reactive intermediates in anodic of water were performed, using p-nitrosodimethylaniline (RNO) as a selective scavenger. At lead dioxide anodes hydroxyl radical OH^. and singlet oxygen ¹O₂ can be found while at platinum anodes singlet oxygen and peroxo compounds, HOO^. or H₂O₂ appear.A mechanism regarding the role of “free” hydroxyl radicals in the formation of ozone at lead dioxide anodes is proposed.     

Analysis of oxidation process of cholecystokinin octapeptide with reactive oxygen species by high‐performance liquid chromatography and subsequent electrospray ionization mass spectrometry

The C‐terminal octapeptide of cholecystokinin (CCK8) includes some easily oxidizable amino acids. The oxidation of CCK8 by reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂) and hydroxyl radicals (OH^?) was investigated using reversed‐phase high performance liquid chromatography (RP‐HPLC) and subsequent electrospray ionization mass spectrometry. The mechanism of oxidation of CCK8 in the H₂O₂ system differed from that of CCK8 in the Fenton system, in which OH^? are produced. In the H₂O₂ system, ²⁸Met and ³¹Met were oxidized to methionine sulfoxide, and no further oxidation or degradation/hydrolysis occurred. On the other hand, in the Fenton system, ²⁸Met and ³¹Met residues were oxidized to methionine sulfone via the formation of methionine sulfoxide. In addition, the oxidized product was observed at the Trp residue but not at the Tyr residue, and small peptide fragments from CCK8 were observed in the Fenton system. From these results, it was concluded that ²⁸Met and ³¹Met residues of CCK8 are susceptible to oxidation by ROS. Copyright © 2009 John Wiley & Sons, Ltd.     

Kinetic Parameters of Alkyl,Alkoxy, and Peroxy Radical Isomerization

The parabolic model of radical abstraction reactions is used to analyze experimental data on monomolecular hydrogen-atom transfer in the reactionsRC^.H(CH₂) _n CH₂R¹ RCH₂(CH₂) _n C^.HR¹(n= 2, 3, 4)RCH(O^.)(CH₂)₂CH₂R¹ RCH(OH)(CH₂)₂C^.HR¹ RCH(OO^.)(CH₂) _n CH₂R¹ RCH(OOH)(CH₂) _n C^.HR¹(n= 1, 2).The activation energies and rate constants that specify each class of these reactions are calculated. Alkyl radical isomerization is characterized by the following activation energies of a thermally neutral reaction depending on the cycle size in the transition state (nis the number of atoms in a cycle): E _{e , 0}(kJ/mol) = 46.6 (n= 6), 59.4 (n= 5), and 57.1 (n= 7). Alkoxy radicals isomerize with E _{e , 0}(kJ/mol) = 53.4 (n= 6), whereas peroxy radicals isomerize with E _{e , 0}(kJ/mol) = 53.2 (n= 6) and E _{e , 0}(kJ/mol) = 54.8 (n= 7). The E _{e , 0}value varies with changes in the cycle size and the strain energy in cycloparaffin C _n H_2n in the same manner. The activation energies E _{e , 0}for the intra- and intermolecular H-atom abstractions are compared. It is found that E _{e , 0}(isomerization) < E _{e , 0}(R^.+ R¹H) for alkyl radicals and that E _{e , 0}(isomerization) E _{e , 0}(RO^.(RO^.) + R¹H) for alkoxy and peroxy radicals.     

The Role of Interfacial Reactions in Determining Plasma–Liquid Chemistry

In this work, we investigate the production of highly oxidative species in solutions exposed to a self-pulsed corona discharge in air. We examine how the properties of the target solution (pH, conductivity) and the discharge power affect the discharge stability and the production of H₂O₂. Indigo carmine, a common organic dye, is used as an indicator of oxidative strength and in particular, hydroxyl radical (OH^·) production. The observed rate of indigo oxidation in contact with the discharge far exceeds that predicted from reactions based on concentrations of species measured in the bulk solution. The generation of H₂O₂ and the oxidation of indigo carmine indicate a high concentration of highly oxidizing species such as OH^· at the plasma–liquid interface. These results indicate that reactions at the air plasma–liquid interface play a dominant role in species oxidation during direct non-equilibrium atmospheric pressure plasma treatment.     

On the Gas‐Phase Reactivity of Complexed OH+ with Halogenated Alkanes

OH⁺ is an extraordinarily strong oxidant. Complexed forms (L? OH⁺), such as H₂OOH⁺, H₃NOH⁺, or iron–porphyrin‐OH⁺ are the anticipated oxidants in many chemical reactions. While these molecules are typically not stable in solution, their isolation can be achieved in the gas phase. We report a systematic survey of the influence on L on the reactivity of L? OH⁺ towards alkanes and halogenated alkanes, showing the tremendous influence of L on the reactivity of L? OH⁺. With the help of with quantum chemical calculations, detailed mechanistic insights on these very general reactions are gained. The gas‐phase pseudo‐first‐order reaction rates of H₂OOH⁺, H₃NOH⁺, and protonated 4‐picoline‐N‐oxide towards isobutane and different halogenated alkanes C_nH_2n+1Cl (n=1–4), HCF₃, CF₄, and CF₂Cl₂ have been determined by means of Fourier transform ion cyclotron resonance meaurements. Reaction rates for H₂OOH⁺ are generally fast (7.2×10^?10–3.0×10^?9 cm³ mol^?1 s^?1) and only in the cases HCF₃ and CF₄ no reactivity is observed. In contrast to this H₃NOH⁺ only reacts with tC₄H₉Cl (k_obs=9.2×10^?10), while 4‐CH₃‐C₅H₄N‐OH⁺ is completely unreactive. While H₂OOH⁺ oxidizes alkanes by an initial hydride abstraction upon formation of a carbocation, it reacts with halogenated alkanes at the chlorine atom. Two mechanistic scenarios, namely oxidation at the halogen atom or proton transfer are found. Accurate proton affinities for HOOH, NH₂OH, a series of alkanes C_nH_2n+2 (n=1–4), and halogenated alkanes C_nH_2n+1Cl (n=1–4), HCF₃, CF₄, and CF₂Cl₂, were calculated by using the G3 method and are in excellent agreement with experimental values, where available. The G3 enthalpies of reaction are also consistent with the observed products. The tendency for oxidation of alkanes by hydride abstraction is expressed in terms of G3 hydride affinities of the corresponding cationic products C_nH_2n+1⁺ (n=1–4) and C_nH_2nCl⁺ (n=1–4). The hypersurface for the reaction of H₂OOH⁺ with CH₃Cl and C₂H₅Cl was calculated at the B3 LYP, MP2, and G3_m* level, underlining the three mechanistic scenarios in which the reaction is either induced by oxidation at the hydrogen or the halogen atom, or by proton transfer.     

Kinetics of oxidation of SCN− by diperiodato cuprate(III) (DPC) in alkaline medium

The kinetics of oxidation of SCN⁻ by DPC has been investigated in alkaline medium. The reaction shows first-order dependence in [SCN⁻]. The pseudo-first-order rate constant (k_obs) changes differently under different [OH⁻]. At low [OH⁻], k_obs decreases when [OH⁻] increases, but when [OH⁻] increases to enough extent, k_obs increases with increase in [OH⁻]. Free radicals were observed in the process of reaction. A plausible mechanism involving Cu(HL)₂ and CuL as active substrates in the reaction has been proposed. The rate equations derived from the mechanism explain all the experimental phenomena satisfactorily. © 1996 John Wiley & Sons, Inc.