NADH Analogues Research Articles

A Chromium(III)‐Superoxo Complex as a Three‐Electron Oxidant with a Large Tunneling Effect in Multi‐Electron Oxidation of NADH Analogues

AbstractMetal‐superoxo species are involved in a variety of enzymatic oxidation reactions, and multi‐electron oxidation of substrates is frequently observed in those enzymatic reactions. A CrIII‐superoxo complex, [CrIII(O2)(TMC)(Cl)]+ (1; TMC=1,4,8,11‐tetramethyl‐1,4,8,11‐tetraazacyclotetradecane), is described that acts as a novel three‐electron oxidant in the oxidation of dihydronicotinamide adenine dinucleotide (NADH) analogues. In the reactions of 1 with NADH analogues, a CrIV‐oxo complex, [CrIV(O)(TMC)(Cl)]+ (2), is formed by a heterolytic O−O bond cleavage of a putative CrII‐hydroperoxo complex, [CrII(OOH)(TMC)(Cl)], which is generated by hydride transfer from NADH analogues to 1. The comparison of the reactivity of NADH analogues with 1 and p‐chloranil (Cl4Q) indicates that oxidation of NADH analogues by 1 proceeds by proton‐coupled electron transfer with a very large tunneling effect (for example, with a kinetic isotope effect of 470 at 233 K), followed by rapid electron transfer.

Catalytic Hydroxylation of Benzene to Phenol by Dioxygen with an NADH Analogue.

Hydroxylation of benzene by molecular oxygen (O2 ) occurs efficiently with 10-methyl-9,10-dihydroacridine (AcrH2 ) as an NADH analogue in the presence of a catalytic amount of Fe(ClO4 )3 or Fe(ClO4 )2 with excess trifluoroacetic acid in a solvent mixture of benzene and acetonitrile (1:1 v/v) to produce phenol, 10-methylacridinium ion and hydrogen peroxide (H2 O2 ) at 298 K. The catalytic oxidation of benzene by O2 with AcrH2 in the presence of a catalytic amount of Fe(ClO4 )3 is started by the formation of H2 O2 from AcrH2 , O2 , and H(+) . Hydroperoxyl radical (HO2 (.) ) is produced from H2 O2 with the redox pair of Fe(3+) /Fe(2+) by a Fenton type reaction. The rate-determining step in the initiation is the proton-coupled electron transfer from Fe(2+) to H2 O2 to produce HO(.) and H2 O. HO(.) abstracts hydrogen rapidly from H2 O2 to produce HO2 (.) and H2 O. The Fe(3+) produced was reduced back to Fe(2+) by H2 O2 . HO2 (.) reacts with benzene to produce the radical adduct, which abstracts hydrogen from AcrH2 to give the corresponding hydroperoxide, accompanied by generation of acridinyl radical (AcrH(.) ) to constitute the radical chain reaction. Hydroperoxyl radical (HO2 (.) ), which was detected by using the spin trap method with EPR analysis, acts as a chain carrier for the two radical chain pathways: one is the benzene hydroxylation with O2 and the second is oxidation of an NADH analogue with O2 to produce H2 O2 .

Establishing the Hydride Donor Abilities of Main Group Hydrides

Interest in reductions with main group hydrides has been reinvigorated with the discovery of frustrated Lewis pairs. Computational analysis showed that the borohydride of the commonly used Lewis acid B(C6F5)3 was determined to be 15 kcal/mol less reducing than borohydride ([BH4]−), 22 kcal/mol less reducing than aluminum hydride ([AlH4]−), and 41 kcal/mol less reducing than superhydride ([HBEt3]−). In addition to [HB(C6F5)3]−, a hydride donor ability scale with an estimated error of ∼3 kcal/mol includes 132 main group hydrides with gradually changing reducing capabilities spanning 160 kcal/mol. The scale includes representatives from organosilanes, organogermanes, organostannanes, borohydrides, boranes, aluminum hydrides, NADH analogues, and CH hydride donors. The large variety of reducing agents and the wide span of the scale (ranging from 0.5 to 160 kcal/mol in acetonitrile) make the scale a useful tool for the future design of metal-based or main group reducing agents.

Modeling of the hydrophobic microenvironment of water-soluble molybdoenzymes in an aqueous micellar solution.

A toluene-soluble molybdenum(vi) complex containing a bulky hydrophobic substituent, (Et4N)2[Mo(VI)O2{1,2-S2-3,6-(RCONH)2C6H2}2] (R = (4-(t)BuC6H4)3C), was dissolved in the hydrophobic core of a micelle in an aqueous medium and catalyzed the biomimetic reduction of an amine N-oxide by an NADH analog. The kinetic isotope effect of solvent water clearly indicates that water molecules are essential for catalysis and are involved in the rate-determining step.

RuV(NCN-Me)(bpy)(=O)]3+ Mediates efficient C–H bond oxidation from NADH analogs in aqueous media rather than water oxidation

[Ru(V)[double bond, length as m-dash]O](3+) and [Ru(VI)[double bond, length as m-dash]O](4+) generated from [Ru(II)(NCN-Me)(bpy)(H2O)](PF6)2 (where NCN-Me is the neutral N-methyl-3,5-di(2-pyridyl)pyridinium iodide after deprotonation of the C-H bond) play a selective role in the C-H bond oxidation of 2-(pyridin-2-yl)-9,10-dihydroacridine (PADHH) and water oxidation, respectively.

Multiple Pathways in the Oxidation of a NADH Analogue

Oxidation of the NADH analogue, N-benzyl-1,4-dihydronicotinamide (BNAH), by the 1e(-) acceptor, [Os(dmb)3](3+), and 2e(-)/2H(+) acceptor, benzoquinone (Q), has been investigated in aqueous solutions over extended pH and buffer concentration ranges by application of a double-mixing stopped-flow technique in order to explore the redox pathways available to this important redox cofactor. Our results indicate that oxidation by quinone is dominated by hydride transfer, and a pathway appears with added acids involving concerted hydride-proton transfer (HPT) in which synchronous transfer of hydride to one O-atom at Q and proton transfer to the second occurs driven by the formation of the stable H2Q product. Oxidation by [Os(dmb)3](3+) occurs by outer-sphere electron transfer including a pathway involving ion-pair preassociation of HPO4(2-) with the complex that may also involve a concerted proton transfer.

Mycobacterium tuberculosis Type II NADH-Menaquinone Oxidoreductase Catalyzes Electron Transfer through a Two-Site Ping-Pong Mechanism and Has Two Quinone-Binding Sites

Type II NADH-quinone oxidoreductase (NDH-2) catalyzes the transfer electrons from NADH to the quinone pool and plays an essential role in the oxidative phosphorylation system of Mycobacterium tuberculosis (Mtb). The absence of NDH-2 in the mammalian mitochondrial electron transport chain makes this enzyme an attractive target for antibiotic development. To fully establish the kinetic properties of this enzyme, we studied the interaction of Mtb NDH-2 with substrates, NADH, and various quinone analogues and their products in both membrane and soluble environments. These studies, and comparative analyses of the kinetics with thio-NAD+ and quinone electron acceptors, provided evidence that Mtb NDH-2 catalyzes the transfer electrons from NADH to quinone substrates by a nonclassical, two-site ping-pong kinetic mechanism whereby substrate quinones bind to a site that is distinct from the NADH-binding site. Furthermore, the effects of quinols on Mtb NDH-2 catalytic activity demonstrate the presence of two binding sites for quinone ligands, one favoring the reduced form and the other favoring the oxidized form.

Hydride transfer from NADH analogues to a nonheme manganese(IV)-oxo complex via rate-determining electron transfer.

Hydride transfer from NADH analogues to a nonheme Mn(iv)-oxo complex, [(Bn-TPEN)Mn(IV)(O)](2+), proceeds via a rate-determining electron transfer step with no deuterium kinetic isotope effect (KIE = 1.0 ± 0.1); a charge-transfer complex formed between the Mn(IV)(O) complex and NADH analogues is involved in the hydride transfer reaction.

ChemInform Abstract: Synthesis of Chiral NADH Analogue Based on Proline Template Including Thiourea and Nicotinic Acid Moieties.

AbstractA chiral reductase‐mimicking catalyst built on proline template incorporating a covalently bound NADH mimic is synthesized by conventional procedures.

Interaction of reduced nicotinamide adenine dinucleotide with an antifreeze protein from Dendroides canadensis: mechanistic implication of antifreeze activity enhancement.

Antifreeze proteins (AFPs) found in many organisms can noncolligatively lower the freezing point of water without altering the melting point. The difference between the depressed freezing point and the melting point, termed thermal hysteresis (TH), is usually a measure of the antifreeze activity of AFPs. Certain low molecular mass molecules and proteins can further enhance the antifreeze activity of AFPs. Interaction between an enhancer and arginine is known to play an important role in enhancing the antifreeze activity of an AFP from the beetle Dendroides canadensis (DAFP-1). Here, we examined the enhancement effects of several prevalent phosphate-containing coenzymes on the antifreeze activity of DAFP-1. β-Nicotinamide adenine dinucleotide (reduced) (NADH) is identified as the most efficient enhancer of DAFP-1, which increases the antifreeze activity of DAFP-1 by around 10 times. Examination of the enhancement abilities of a series of NADH analogs and various molecular fragments of NADH reveals that the modifications of nicotinamide generate a series of highly efficient enhancers, though none as effective as NADH itself, and the whole molecular structure of NADH is necessary for its highly efficient enhancement effect. We also demonstrated a 1:1 binding between DAFP-1 and NADH. The binding was characterized by high-performance liquid chromatography (HPLC) using the gel filtration method of Hummel and Dreyer. The data analysis suggests binding between DAFP-1 and NADH with a dissociation constant in the micromolar range. Interactions between DAFP-1 and NADH are discussed along with molecular mechanisms of enhancer action.

Synthesis of Chiral NADH Analog Based on Proline Template Including Thiourea and Nicotinic Acid Moieties

Chiral reductase-mimicking organic molecule built on proline template incorporating a covalently bound NADH mimic via thiourea, and related reducing agent Hantzsch dihydropyridine, was designed. A synthetic path was developed involving interlinking of chiral proline derivatives with thiourea and subsequent coupling reaction with nicotinoyl chloride. The structure of target compound was studied by x–ray, indicating a double H bond with thiourea hydrogens and oxygen O1 of benzylcarbamate fragment. The reduction of benzil and imines was performed.

Cupric superoxo-mediated intermolecular C-H activation chemistry.

The new cupric superoxo complex [LCu(II)(O(2)(•-))](+), which possesses particularly strong O-O and Cu-O bonding, is capable of intermolecular C-H activation of the NADH analogue 1-benzyl-1,4-dihydronicotinamide (BNAH). Kinetic studies indicated a first-order dependence on both the Cu complex and BNAH with a deuterium kinetic isotope effect (KIE) of 12.1, similar to that observed for certain copper monooxygenases.

Electron- and Hydride-Transfer Reactivity of an Isolable Manganese(V)−Oxo Complex

The electron-transfer and hydride-transfer properties of an isolated manganese(V)−oxo complex, (TBP8Cz)Mn(V)(O) (1) (TBP8Cz = octa-tert-butylphenylcorrolazinato) were determined by spectroscopic and kinetic methods. The manganese(V)−oxo complex 1 reacts rapidly with a series of ferrocene derivatives ([Fe(C5H4Me)2], [Fe(C5HMe4)2], and ([Fe(C5Me5)2] = Fc*) to give the direct formation of [(TBP8Cz)Mn(III)(OH)]− ([2-OH]−), a two-electron-reduced product. The stoichiometry of these electron-transfer reactions was found to be (Fc derivative)/1 = 2:1 by spectral titration. The rate constants of electron transfer from ferrocene derivatives to 1 at room temperature in benzonitrile were obtained, and the successful application of Marcus theory allowed for the determination of the reorganization energies (λ) of electron transfer. The λ values of electron transfer from the ferrocene derivatives to 1 are lower than those reported for a manganese(IV)−oxo porphyrin. The presumed one-electron-reduced intermediate, a Mn(IV) complex, was not observed during the reduction of 1. However, a Mn(IV) complex was successfully generated via one-electron oxidation of the Mn(III) precursor complex 2 to give [(TBP8Cz)Mn(IV)]+ (3). Complex 3 exhibits a characteristic absorption band at λ(max) = 722 nm and an EPR spectrum at 15 K with g(max)′ = 4.68, g(mid)′ = 3.28, and g(min)′ = 1.94, with well-resolved 55Mn hyperfine coupling, indicative of a d3 Mn(IV)S = 3/2 ground state. Although electron transfer from [Fe(C5H4Me)2] to 1 is endergonic (uphill), two-electron reduction of 1 is made possible in the presence of proton donors (e.g., CH3CO2H, CF3CH2OH, and CH3OH). In the case of CH3CO2H, saturation behavior for the rate constants of electron transfer (k(et)) versus acid concentration was observed, providing insight into the critical involvement of H+ in the mechanism of electron transfer. Complex 1 was also shown to be competent to oxidize a series of dihydronicotinamide adenine dinucleotide (NADH) analogues via formal hydride transfer to produce the corresponding NAD+ analogues and [2-OH]−. The logarithms of the observed second-order rate constants of hydride transfer (k(H)) from NADH analogues to 1 are linearly correlated with those of hydride transfer from the same series of NADH analogues to p-chloranil.

ChemInform Abstract: Oxidation of 10-Methylacridan, a Synthetic Analogue of NADH, and Deprotonation of Its Cation Radical. Convergent Application of Laser Flash Photolysis and Direct and Redox Catalyzed Electrochemistry to the Kinetics of Deprotonation of

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: General Acid Catalysis of the Reduction of p-Benzoquinone by an NADH Analogue

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Acid-Catalyzed Photoreduction of Dialkyl Sulfoxides by an Acid-Stable NADH Analogue.

Photoreduction of dialkyl sulfoxides (R 2 SO) by an acid-stable NADH analogue, 10-methyl-9,10-dihydroacridine (AcrH 2 ), proceeds in the presence of perchloric acid in acetonitrile containing H 2 O (0.50 M) to yield 10-methylacridinium ion (AcrH + ) and the corresponding dialkyl sulfides (R 2 S). No photoreduction of R 2 SO by AcrH 2 has occurred in the absence of perchloric acid

Mechanistic Insights into Hydride-Transfer and Electron-Transfer Reactions by a Manganese(IV)−Oxo Porphyrin Complex

Hydride transfer from dihydronicotinamide adenine dinucleotide (NADH) analogs to a manganese(IV)-oxo porphyrin complex, (TMP)Mn(IV)(O) [TMP = 5,10,15,20-tetrakis(2,4,6-trimethylphenyl)porphyrin], occurs via disproportionation of (TMP)Mn(IV)(O) to [(TMP)Mn(III)](+) and [(TMP)Mn(V)(O)](+) that acts as the actual hydride acceptor. In contrast, electron transfer from ferrocene derivatives to (TMP)Mn(IV)(O) occurs directly to afford ferricenium ions and (TMP)Mn(III)(OH) products. The disproportionation rate constant of (TMP)Mn(IV)(O) was determined by the dependence of the observed second-order rate constants on concentrations of NADH analogs to be (8.0 +/- 0.6) x 10(6) M(-1) s(-1) in acetonitrile at 298 K. The disproportionation rate constant of (TMP)Mn(IV)(O) in hydride-transfer reactions increases linearly with increasing acid concentration, whereas the rate constant of electron transfer from ferrocene to (TMP)Mn(IV)(O) remains constant irrespective of the acid concentration. The rate constants of electron transfer from a series of ferrocene derivatives to (TMP)Mn(IV)(O) were evaluated in light of the Marcus theory of electron transfer to determine the reorganization energy of electron transfer by the (TMP)Mn(IV)(O) complex.

Dioxygen Activation by Mononuclear Nonheme Iron(II) Complexes Generates Iron−Oxygen Intermediates in the Presence of an NADH Analogue and Proton

One primary goal in biomimetic research is to understand mechanisms of dioxygen activation, structures of reactive intermediates, and reactivities of the intermediates involved in catalytic oxidation reactions by metalloenzymes, such as heme and nonheme iron oxygenases. In this communication, we have reported the first example of generating nonheme iron(III)-hydroperoxo and iron(IV)-oxo complexes by activating O(2) with a biologically important electron donor, an NADH analogue, and an acid. The formation of iron(III)-hydroperoxo and iron(IV)-oxo complexes was found to depend on the supporting ligands. We have also demonstrated that high-spin nonheme iron(II) complexes with a low oxidation potential are able to bind and activate O(2) to generate the iron-oxygen intermediates.

Evaluation of NAD(H) Analogues as Selective Inhibitors for Trypanosoma Cruzi S-Adenosylhomocysteine Hydrolase

S-Adenosylhomocysteine (AdoHcy) hydrolases (SAHHs) from human sources (Hs-SAHHs) bind the cofactor NAD+ more tightly than several parasitic SAHHs by around 1000-fold. This property suggests the cofactor binding site of this essential enzyme as a potential anti-parasitic drug target, e.g., against SAHH from Trypansoma cruzi (Tc-SAHH). The on-rate and off-rate constants and the equilibrium dissociation constants were determined for NAD+/NADH analogues and suggested that NADH analogues were the most promising for selective inhibition of Tc-SAHH. None significantly inhibited Hs-SAHH while S-NADH and H-NADH (see Figure 1) reduced the catalytic activity of Tc-SAHH to < 10% in six minutes of exposure.

Sequential Electron-Transfer and Proton-Transfer Pathways in Hydride-Transfer Reactions from Dihydronicotinamide Adenine Dinucleotide Analogues to Non-heme Oxoiron(IV) Complexes and p-Chloranil. Detection of Radical Cations of NADH Analogues in Acid-Promoted Hydride-Transfer Reactions

Hydride transfer from dihydronicotinamide adenine dinucleotide (NADH) analogues, such as 10-methyl-9,10-dihydroacridine (AcrH 2) and its derivatives, 1-benzyl-1,4-dihydronicotinamide (BNAH), and their deuterated compounds, to non-heme oxoiron(IV) complexes such as [(L)Fe (IV)(O)] (2+) (L = N4Py, Bn-TPEN, and TMC) occurs to yield the corresponding NAD (+) analogues and non-heme iron(II) complexes in acetonitrile. Hydride transfer from the NADH analogues to p-chloranil (Cl 4Q) also occurs to produce the corresponding NAD (+) analogues and the hydroquinone anion (Cl 4QH (-)). The logarithms of the observed second-order rate constants (log k H) of hydride transfer from NADH analogues to non-heme oxoiron(IV) complexes are linearly correlated with those of hydride transfer from the same series of NADH analogues to Cl 4Q, including similar kinetic deuterium isotope effects. The log k H values of hydride transfer from NADH analogues to non-heme oxoiron(IV) complexes are also linearly correlated with those of deprotonation of the radical cations of NADH analogues. Such linear correlations indicate that overall hydride-transfer reactions of NADH analogues to both non-heme oxoiron(IV) complexes and Cl 4Q occur via electron transfer from NADH analogues to the oxoiron(IV) complexes, followed by rate-limiting deprotonation from the radical cations of NADH analogues and subsequent rapid electron transfer from the deprotonated radicals to the Fe(III) complexes to yield the corresponding NAD (+) analogues and the Fe(II) complexes. The electron-transfer pathway was accelerated by the presence of perchloric acid, and the resulting radical cations of NADH analogues were detected by electron spin resonance spectroscopy and UV-vis spectrophotometry in the acid-promoted hydride-transfer reactions from NADH analogues to non-heme oxoiron(IV) complexes. This result provides the first direct evidence that a hydride transfer from NADH analogues to non-heme oxoiron(IV) complexes proceeds via an electron-transfer pathway.