NADH Model Compound Research Articles

Chiral NADH model systems functionalized with Zn(II)-cyclen as flavin binding site

A series of chiral peptides has been prepared, bearing a 1,4-dihydronicotine amide and a zinc cyclen moiety. The metal complex reversibly binds flavins in aqueous solution, while the dihydronicotine amide serves as a NADH model transferring a hydride to the flavin within the assembly. The reaction rate of the redox reaction was monitored and determined by UV spectroscopy. The reaction rates of the substituted compounds were slower if compared to the non-substituted parent compound 1- H , but still show a 30–100 fold rate enhancement compared to the compound missing a flavin binding site. It was anticipated to probe the cryptic stereoselectivity of the hydride transfer from dihydropyridine to flavin. Spectroscopic data indicate that the introduction of deuterium labels upon reduction of the pyridinium salts to 1,4-dihydropyridine in D 2O proceeds diastereoselectively, but identical isotope effects on the rate of flavin reduction as with a non-chiral NADH model revealed that the hydride transfer within the assembly proceeds not stereoselective. A more rigid chiral NADH model compound must be prepared to achieve this goal.

Carbonyl orientation determines regio- and enantioselectivity in 1,2-/1,4-reduction of an NAD model compound.

An optically active, axially chiral NAD model compound(1) with a quinoline ring system was reduced by the chiral NADH model compound (4), affording a mixture of 1,2- and 1,4-dihydroquinolines. The carbonyl orientation governs the molecular arrangement in the transition state of the reaction and determines the regio- and enantioselectivity of the product.

Excited‐State Behavior and Photoionization of 1,8‐Acridinedione Dyes in Micelles—Comparison with NADH Oxidation

The photophysics and photochemistry of 1,8-acridinedione dyes, which are analogues of reduced nicotinamide adenine dinucleotide (NADH), are studied in anionic and cationic micelles. Acridinedione dyes (ADDs) are solubilized in micelles at the micelle-water interface and are in equilibrium between the aqueous and micellar phase. The binding of the ADDs with micelles is attributed to hydrophobic interactions and the binding constants are determined with steady-state and time-resolved techniques. Nanosecond laser flash photolysis studies are carried out in aqueous, anionic, and cationic micellar solutions. The ADD undergoes photoionization in the excited state to give a solvated electron. The solvated electron reacts with the ADD to give an anion radical. In anionic micelles, the yield of the solvated electron increases because of the efficient separation of the cation radical and the electron. Cation radicals derived from the photooxidation of ADDs are involved in keto-enol tautomerization. Under acidic conditions, an enol radical cation of the acridinedione dye is formed from the keto form of the cation radical by intramolecular hydrogen atom transfer. In cationic micelles, due to electrostatic attraction, the electron cannot escape from the micelle and recombination of the cation radical and the electron results in the formation of a triplet state. For the first time, a solvated electron is observed in the laser flash photolysis of ADDs in anionic micelles. The photoionization of ADDs depends on the excitation wavelength and is biphotonic at 355 nm and monophotonic at 248 nm. From the results with this NADH model compound, the sequential electron-proton-electron transfer oxidation of NADH is confirmed and the nature of the intermediates involved in the oxidation is unraveled; these intermediates are found to depend on the pH value of the medium.

Hydride-exchange reactions between NADH and NAD+ model compounds under non-steady-state conditions. Apparent and real kinetic isotope effects.

The kinetics of the hydride exchange reaction between NADH model compound 10-methyl-9,10-dihydroacridine (MAH) and 1-benzyl-3-cyanoquinolinium (BQCN+) ion in acetonitrile were studied at temperatures ranging from 291 to 325 K. The extent of reaction-time profiles during the first half-lives are compared with theoretical data for the simple single-step mechanism and a 2-step mechanism involving initial donor/acceptor complex formation followed by unimolecular hydride transfer. The profiles for the reactions of MAH deviate significantly from those expected for the simple single-step mechanism with the deviation increasing with increasing temperature. The deviation from simple mechanism behavior is much less pronounced for the reactions of 10-methyl-9,10-dihydroacridine-10,10-d2 (MAD) which gives rise to extent of reaction dependent apparent kinetic isotope effects (KIEapp). Excellent fits of the experimental extent of reaction-time profiles with theoretical data for the 2-step mechanism, in the pre-steady-state time period, were observed in all cases. Resolution of the kinetics of the hydride exchange reaction into the microscopic rate constants over the entire temperature range resulted in real kinetic isotope effects for the hydride transfer step ranging from 40 (291 K) to 8.2 (325 K). That the reaction involves significant hydride tunnelling was verified by the magnitudes of the Arrhenius parameters; Ea D - EaH = 8.7 kcal mol-1 and AD/AH = 8 x 10(4). An electron donor acceptor complex (lambda max = 526 nm) was observed to be a reaction intermediate. Theoretical extent of reaction-time profile data are discussed for the case where a reaction intermediate is formed in a non-productive side equilibrium as compared to the case where it is a real intermediate on the reaction coordinate between reactants and products. The common assumption that the two cases are kinetically indistinguishable is shown to be incorrect.

NAD/NADH models with axial/central chiralities: superiority of the quinoline ring system.

Precursors of NAD model compounds 1c and 3a,b were successfully resolved into their atropisomers with respect to carbamoyl rotation. Atropisomers of quinoline derivatives are much more stable than pyridine derivatives as determined by cyclic voltammetry and X-ray crystallography. The 1,4-reduction of NAD model compound 4 was successfully achieved, affording novel NADH model compound 5. The rotational properties of the side chain of 5 were investigated by means of dynamic NMR. The rotational rate and syn/anti ratio, which indicate the orientation between carbonyl oxygen and hydrogen at the 4-position, are significantly affected by addition of magnesium ion. In the rotational transition state, the double-bond character of the C(carbonyl)-N(amide) bond is disrupted judging from the activation parameters. The oxidation of chiral 5 with p-benzoquinone in the presence of magnesium ion catalyst gave predominantly one enantiomer of 4. On the other hand, oxidation of 5 with p-chloranil (tetrachloro-p-benzoquinone) in the absence of magnesium ions affords the opposite enantiomer of 4 as the major product. The product enantiomer ratio is parallel to the syn/anti ratio in the starting material, indicating the importance of ground state conformation to stereochemistry of the reaction.

Highly reactive and stereospecific reaction of quinoline-type NADH model compounds with methyl benzoylformate

NADH model compounds with a dihydroquinoline ring can reduce methyl benzoylformate with very high reactivity and stereospecificity. Chiral column HPLC is effective in the separation and analysis of enantiomers of NADH and NAD model compounds, respectively.

Hydrogen-Transferred Radical Cations of NADH Model Compounds. 2. Sequential Electron−Proton Addition to NAD+

Sequential electron−proton addition to different NAD+ model compounds was studied by pulse radiolysis. Under mildly acidic conditions, the radicals obtained by reduction of the cations are protonated at the carbonyl group. The pKa values of the resulting enol radical cations were determined. The same enol radical cations can also be formed via a deprotonation−reprotonation process from the keto radical cations of the corresponding NADH model compounds.

Hydrogen-Transferred Radical Cations of NADH Model Compounds. 3. 1,8-Acridinediones

Two different tautomeric forms of radical cations generated from 1,8-acridinediones were characterized by steady-state methods, pulse radiolysis, and laser flash photolysis techniques. In solution the primarily formed keto radical cations tautomerize in less than 1 ns to the corresponding enol radical cations. This process is significantly retarded in cryogenic glasses.

Hydrogen-Transferred Radical Cations of NADH Model Compounds. 1. Spontaneous Tautomerization

The radical cations generated from three NADH model compounds were investigated with particular emphasis on the possible formation of tautomeric enol radical cations. To a small extent, hydrogen transfer occurs upon ionization of all three compounds in argon matrixes. In the bicyclic seven-membered ring derivative enolization continues in a thermal reaction at 12 K (with highly dispersive kinetics), or upon visible irradiation. These processes are not observed in methylcyclohexane glasses at 77 K, which indicates that a cage effect is preventing the attainment of a reactive conformation in this medium. The assignment of electronic spectra of the primary (keto) cations and of their tautomeric (enol) forms is supported by CASSCF/CASPT2 and TD-B3LYP calculations.

補酵素ＮＡＤモデル分子を用いた生体酸化・不斉還元モデル反応

Coenzyme NAD+/NADH, a major cofactor of dehydrogenases, functions as an autorecycling redox agent in biological systems, which is exemplified by enantioselective reduction of pyruvate to L-lactate and oxidation of glyceraldehyde-3-phosphate to 1, 3-bisphosphoglycerate as is observed in anaerobic glycolysis. This article reviews biomimetic asymmetric reduction and oxidation in NAD+/NADH model systems. The first part outlines highly enantioselective reduction of benzoylformate, a lactate analog, with representative NADH model compounds mimicking biological reduction in lactate dehydrogenase. In this section, the well-developed model reactions are grouped based on the types of NADH models ; one having a chiral center at the C-4 position of its 1, 4-dihydronicotinoyl ring and the other good for recycling use. The latter half describes the detailed history on the less developed biomimetic oxidation with NAD+ model compounds. This section classifies the model reactions based on the types of model substrates to summarize the oxidation of alcohols, aldehydes, and formates into aldehydes (or ketones), carboxylates, and carbon dioxide, respectively, with regioselective formation of the corresponding NADH model compounds as analogous reactions in alcohol-, glyceraldehyde-3-phosphate-, and formate dehydrogenases

The kinetics of the reduction of the lipophilic quinone avarone by N-alkyl-1,4-dihydronicotinamides of various lipophilicities

Several NADH model compounds, N-alkyl-1,4-dihydronicotinamides, some of them possessing amphiphilic properties, have been synthesized, and the kinetics of their reaction with a biologically active liphophilic quinone, avarone, has been studied in a protic solvent both in the presence and absence of cationic, anionic or non-ionic surfactants. In the absence of micellar agents, the medium- and long-chain N-dodecyl (3) and N-heptadecyl (4) derivatives show a significant increase in the reaction rates compared to other model compounds, due to the stabilization of the semiquinone intermediate. Anionic surfactants retard the reaction, non-ionic surfactants slightly accelerate the reaction with the short-chain derivatives, and retard the reaction with the medium- and long-chain derivatives, and the cationic surfactants increase the reaction rate with all derivatives except the long-chain 4. The results support the e-p-e mechanism of the reduction of lipophilic quinones byNADHmodels in protic medium.

Energetics of Multistep versus One-step Hydride Transfer Reactions of Reduced Nicotinamide Adenine Dinucleotide (NADH) Models with Organic Cations and p-Quinones.

Free energy changes of each elementary step involved in the formal hydride transfer (H(-)(T)) reactions (including the so-called "one-step" H(-)(T) and "multistep" H(-)(T) mechanisms) of the reduced nicotinamide adenine dinucleotide (NADH) models with various cations and quinones (17) were investigated either by direct thermodynamic measurements or by calculations from thermochemical cycles. Based on the energetic data thus derived, combined with kinetic observations (particularly kinetic isotope effects), the mechanistic characteristics of the NADH-mediated reductions were systematically analyzed. Practical guidelines that resulted from these analyses suggest that a mutistep mechanism (e(-)-H(*) or e(-)-H(+)-e(-)) would be followed if the energy gap of the initial electron transfer [DeltaG(e(-)(T))] between the NADH model compound and the reducing substrate is considerably smaller than the empirical critical limit of 1.0 V for an endothermic e(-)(T). In contrast, if DeltaG(e(-)(T)) is much greater than 1.0 V, a concerted one-step H(-)(T) may take place. The guideline also suggests that a "hybrid" mechanism is possible if the DeltaG(e(-)(T)) is in an intermdiate situation.

Biomimetic Oxidation of Aldehyde with NAD+ Models: Glycolysis-Type Hydrogen Transfer in an NAD+ /NADH Model System.

Just like in biological systems, the GAPDH-catalyzed oxidation of aldehyde to carboxylate proceeds in conjunction with 1,4-selective reduction of NAD+ to NADH model compounds [Eq. (1)]. The combination of GAPDH- and LDH-type transfer reactions is also described here as a system mimic for the NAD+ /NADH redox cycle in anaerobic glycolysis. GAPDH=D-glyceraldehyde-3-phosphate dehydrogenase, LDH=L-lactate dehydrogenase.

ChemInform Abstract: Studies on Novel and Chiral 1,4‐Dihydropyridines. Part 2. Syntheses of 1‐Substituted (SS)‐3‐p‐Tolylsulfinyl‐1,4‐dihydropyridines, Chiral NADH Model Compounds.

AbstractChemInform 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: Studies on Novel and Chiral 1,4‐Dihydropyridines. Part 3. Asymmetric Reduction of Some Ketones with Novel NADH Model Compounds, (SS)‐3‐(p‐ Tolylsulfinyl)‐1,4‐dihydropyridines.

AbstractChemInform 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.

Studies on novel and chiral 1,4-dihydropyridines. IV. Mechanistic aspects of the asymmetric reduction with chiral NADH model compounds, ( SS)-3-( p-tolylsulfinyl)-1,4-dihydropyridines

In the reduction of ketones with NADH mimics, ( S S )-1-substituted 3-( p-tolylsulfinyl)-1,4-dihydropyridines 1, the stereospecific transfer of one of the C-4 hydrogens, which is syn to the SO bond, was experimentally revealed to be involved by employing the 2-methyl derivative 2 and the 4-deuterated derivatives 3a and 3b. The transition state model of this reaction was also proposed by consideration of the results obtained.

Studies on novel and chiral 1,4-dihydropyridines. III. Asymmetric reduction of some ketones with novel NADH model compounds, ( SS)-3-( p-Tolylsulfinyl)-1,4-dihydropyridines

The reactions of the novel NADH model compounds 2 with methyl benzoylformate and some other ketonic compounds were studied. The 3-( p-tolylsulfinyl) derivaties 2 successfully reduced methyl bezoylformate to give methyl ( R)-mandelate in good chemical and optical yields. Some other ketones were also found to be reduced with the compound 2b. A possible transition state model is discussed.

Stereospecific 4-Hydrogen Transfer in the Asymmetric Reduction Using (SS)-3-(p-Tolylsulfinyl)-1,4-dihydropyridines, NADH Model Compounds

Abstract In asymmetric reduction of ketones with (SS)-1-benzyl-3-(p-tolylsulfinyl)-1,4-dihydropyridine as a NADH model compound, a stereospecific transfer of the 4-hydrogen was experimentally proved by the use of the 2-methyl congener and the 4-deuterated derivatives.

ChemInform Abstract: Studies on Novel and Chiral 1,4‐Dihydropyridines. Part 1. Synthesis and Conformational Analysis of Novel NADH Model Compounds, N‐ Substituted (S)‐3‐(p‐Tolylsulfinyl)‐1,4‐dihydropyridines.

AbstractChemInform 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.

A new type of NADH model compound: Synthesis and reactions

Four diastereomeric NADH model compounds were synthesized by the reaction of a pinyl substituted Hantzsch ester with dimethylaluminum amide. The reduction of methyl benzoylformate with these models gave both enantiomers of methyl mandelate.