Suicide inactivation of dioldehydratase by glycolaldehyde and chloroacetaldehyde: an examination of the reaction mechanism

High-level ab initio calculations have been used to study the mechanism for the inactivation of diol dehydratase (DDH) by glycolaldehyde or 2-chloroacetaldehyde. As in the case of the catalytic substrates of DDH, e.g., ethane-1,2-diol, the 5'-deoxyadenosyl radical (Ado*) is able to abstract a hydrogen atom from both substrate analogues in the initial step on the reaction pathway, as evidenced by comparable energy barriers. However, in subsequent step(s), each substrate analogue produces the highly stable glycolaldehyde radical. The barrier for hydrogen atom reabstraction by the glycolaldehyde radical is calculated to be too high ( approximately 110 kJ mol-1) to allow Ado* to be regenerated and recombine with the cob(II)alamin radical, the latter therefore remaining tightly bound to DDH. As a consequence, the catalytic pathway is disrupted, and DDH becomes an impotent enzyme. Interconversion of equivalent structures of the glycolaldehyde radical via the symmetrical cis-ethanesemidione radical is calculated to require 38 kJ mol-1. EPR indications of a symmetrical cis-ethanesemidione structure are likely to be the result of formation of an equilibrium mixture of glycolaldehyde radical structures, this equilibration being facilitated by partial deprotonation of the glycolaldehyde radical by the carboxylate of an amino acid residue within the active site of DDH.     

The vinyloxonium cation (CH2CHOH2+)

Ab initio Molecular orbital calculations with large basis sets and incorporating correlation are used to examine the structures and relative energies of the vinyloxonium (CH₂CHOH₂⁺) and 1-hydroxyethyl (CH₃CHOH⁺) cations. The best structure of the vinyloxonium ion has the OH₂ plane perpendicular to the CCO plane. The energy difference between the vinyloxonium and 1-hydroxyethyl cations is predicted to be 92 kJ mol^?1, substantially greater than a recent experimental estimate of 41 ± 12 kJ mol^?1     

Quinazolines and 1,4-benzodiazepines. LXI. Syntheses of 7-Acetyl-1,4-benzodiazepines

Methods for the synthesis of the biologically active 7-acetyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ( 6 ) are described. This includes two new methods for the preparation of 5-acetyl-2-aminobenzophenone ( 4 ). The crucial steps in these syntheses involve, respectively, the oxidation of an ethyl group to an acetyl group with permanganate or ceric ions ( 2 → 3; 5 → 6 ), the selective reaction of methyl lithium with the cyano group of 7-cyano-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ( 8 ) and the efficient condensation of benzyl cyanide with the ethylene ketal of p-nitroacetophenone to form the anthranil 11 .     

Universal properties of maps of the circle with ɛ-singularities

Following the work of Collet, Eckmann, and Lanford on the Feigenbaum conjecture, we study the structure of the renormalization transformation introduced in [12] upon maps of the circle with critical points of the formx|x|^?.     

Structure and reactivity of bis(silyl) dihydride complexes (PMe(3))(3)Ru(SiR(3))(2)(H)(2): model compounds and real intermediates in a dehydrogenative C-Si bond forming reaction

A series of stable complexes, (PMe(3))(3)Ru(SiR(3))(2)(H)(2) ((SiR(3))(2) = (SiH(2)Ph)(2), 3a; (SiHPh(2))(2), 3b; (SiMe(2)CH(2)CH(2)SiMe(2)), 3c), has been synthesized by the reaction of hydridosilanes with (PMe(3))(3)Ru(SiMe(3))H(3) or (PMe(3))(4)Ru(SiMe(3))H. Compounds 3a and 3c adopt overall pentagonal bipyramidal geometries in solution and the solid state, with phosphine and silyl ligands defining trigonal bipyramids and ruthenium hydrides arranged in the equatorial plane. Compound 3a exhibits meridional phosphines, with both silyl ligands equatorial, whereas the constraints of the chelate in 3c result in both axial and equatorial silyl environments and facial phosphines. Although there is no evidence for agostic Si-H interactions in 3a and 3b, the equatorial silyl group in 3c is in close contact with one hydride (1.81(4) A) and is moderately close to the other hydride (2.15(3) A) in the solid state and solution (nu(Ru.H.Si) = 1740 cm(-)(1) and nu(RuH) = 1940 cm(-)(1)). The analogous bis(silyl) dihydride, (PMe(3))(3)Ru(SiMe(3))(2)(H)(2) (3d), is not stable at room temperature, but can be generated in situ at low temperature from the 16e(-) complex (PMe(3))(3)Ru(SiMe(3))H (1) and HSiMe(3). Complexes 3b and 3d have been characterized by multinuclear, variable temperature NMR and appear to be isostructural with 3a. All four complexes exhibit dynamic NMR spectra, but the slow exchange limit could not be observed for 3c. Treatment of 1 with HSiMe(3) at room temperature leads to formation of (PMe(3))(3)Ru(SiMe(2)CH(2)SiMe(3))H(3) (4b) via a CH functionalization process critical to catalytic dehydrocoupling of HSiMe(3) at higher temperatures. Closer inspection of this reaction between -110 and -10 degrees C by NMR reveals a plethora of silyl hydride phosphine complexes formed by ligand redistribution prior to CH activation. Above ca. 0 degrees C this mixture converts cleanly via silane dehydrogenation to the very stable tris(phosphine) trihydride carbosilyl complex 4b. The structure of 4b was determined crystallographically and exhibits a tetrahedral P(3)Si environment around the metal with the three hydrides adjacent to silicon and capping the P(2)Si faces. Although strong Si.HRu interactions are not indicated in the structure or by IR, the HSi distances (2.00(4) - 2.09(4) A) and average coupling constant (J(SiH) = 25 Hz) suggest some degree of nonclassical SiH bonding in the RuH(3)Si moiety. The least hindered complex, 3a, reacts with carbon monoxide principally via an H(2) elimination pathway to yield mer-(PMe(3))(3)(CO)Ru(SiH(2)Ph)(2), with SiH elimination as a minor process. However, only SiH elimination and formation of (PMe(3))(3)(CO)Ru(SiR(3))H is observed for 3b-d. The most hindered bis(silyl) complex, 3d, is extremely labile and even in the absence of CO undergoes SiH reductive elimination to generate the 16e(-) species 1 (DeltaH(SiH)(-)(elim) = 11.0 +/- 0.6 kcal x mol(-)(1) and DeltaS(SiH)(-)(elim) = 40 +/- 2 cal x mol(-)(1) x K(-)(1); Delta = 9.2 +/- 0.8 kcal x mol(-)(1) and Delta = 9 +/- 3 cal x mol(-)(1).K(-)(1)). The minimum barrier for the H(2) reductive elimination can be estimated, and is higher than that for silane elimination at temperatures above ca. -50 degrees C. The thermodynamic preferences for oxidative additions to 1 are dominated by entropy contributions and steric effects. Addition of H(2) is by far most favorable, whereas the relative aptitudes for intramolecular silyl CH activation and intermolecular SiH addition are strongly dependent on temperature (DeltaH(SiH)(-)(add) = -11.0 +/- 0.6 kcal x mol(-)(1) and DeltaS(SiH)(-)(add) = -40 +/- 2 cal.mol(-)(1) x K(-)(1); DeltaH(beta)(-CH)(-)(add) = -2.7 +/- 0.3 kcal x mol(-)(1) and DeltaS(beta)(-CH)(-)(add) = -6 +/- 1 cal x mol(-)(1) x K(-)(1)). Kinetic preferences for oxidative additions to 1 - intermolecular SiH and intramolecular CH - have been also quantified: Delta = -1.8 +/- 0.8 kcal x mol(-)(1) and Delta = -31 +/- 3 cal x mol(-)(1).K(-)(1); Delta = 16.4 +/- 0.6 kcal x mol(-)(1) and Delta = -13 +/- 6 cal x mol(-)(1).K(-)(1). The relative enthalpies of activation (-)(1) x K(-)(1)). Kinetic preferences for oxidative additions to 1 - intermolecular SiH and intramolecular CH - have been also quantified: Delta (H)SiH(add) = 1.8 +/- 0.8 kcal x mol(-)(1) and Delta S((SiH-add) =31+/- 3 cal x mol(-)(1) x K(-)(1); Delta S (SiH -add) = 16.4 +/- 0.6 kcal x mol(-)(1) and =Delta S (SiH -CH -add) =13+/- 6 cal x mol(-)(1) x K(-)(1). The relative enthalpies of activation are interpreted in terms of strong SiH sigma-complex formation - and much weaker CH coordination - in the transition state for oxidative addition.     

A theoretical approach to substituent effects. A comparison of the isoelectronic BH,CH3, and NH groups and their interaction with substituents in disubstituted benzenes

Ab initio molecular orbital theory with the STO -3G basis set is used to examine both charge and energy interactions in a series of meta- and para-substituted phenylborate anions and toluenes. Comparison of the results is made with data for substituted anilinium cations. It is concluded that whereas NH is a powerful σ acceptor, with essentially no π interaction, BH is primarily a π donor, and, to a slight extent only, a π donor. CH₃ is indicated to be both a weak σ and π donor. Energies of interaction of BH and NH with a series of substituents are an order of magnitude larger than corresponding values for CH₃. Interaction energies for BH are of opposite sign to those for NH. The results may be understood qualitatively using perturbation molecular orbital (PMO ) theory.     

Synthesis of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-α]- pyrrolo[2,1-c][1,4]benzodiazepines

1,3,4,14b-Tetrahydro-2H,10H-pyrazino[1,2-α]pyrrolo[2,1-c] [1,4]benzodiazepines (1a-e) were synthesized to investigate their potential CNS activity. The key step in the synthesis was the formation of the 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (13) by reduction and concomitant cyclization of the nitroketone (11). Biological evaluation of 1a-e revealed interesting properties for 1b (CGS 7525A) [2].     

Aureomycin nitrate,its preparation and identification

Summary Aureomycin hydrochloride does not show any promise as a reagent for qualitative detection or quantitative estimation of any of the common cations or aidons. The well developed crystals of the rather insoluble nitrate may be used for the identification of aureomycin. The low solubility of the nitrate may give a better stability as compared with the hydrochloride, which would be of interest to the pharmacist.

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Zusammenfassung Versuche mit Aureomycinhydrochlorid gaben keine Anhaltspunkte für eine Eignung dieser Verbindung als Reagens für die Auffindung oder Bestimmung der häufig angetroffenen Kationen oder Anionen. Die gut ausgebildeten Kristalle des wenig löslichen Nitrats können für die Erkennung von Aureomycin benützt werden. Die geringe Löslichkeit des Nitrats erhöht dessen Beständigkeit im Vergleich zum Hydrochlorid, was für Pharmazeuten von Interesse sein könnte.

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Résumé Le chlorhydrate d'auréomycine ne montre aucune propriété intéressante comme réactif de recherche qualitative ou d'estimation quantitative des cations et anions courants. On peut utiliser les cristaux bien développés de son nitrate assez peu soluble pour identifier l'auréomycine. La faible solubilité de ce nitrate peut lui conférer une meilleure stabilité que celle du chlorure ce qui est digne d'intérêt pour les pharmaciens.

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Dedicated to Prof. Dr.Hans Lieb at his 70th birthday.     

The use of comet assay data with a simple reaction mechanism to evaluate the relative effectiveness of free radical scavenging by quercetin, epigallocatechin gallate and N-acetylcysteine in UV-irradiated MRC5 lung fibroblasts

Comet assay data (tail DNA %) have been gathered for the concentration dependent role of three antioxidants (AOs); quercetin (Q), epigallocatechin gallate (EGCG) and N-acetylcysteine (NAC) in reducing UV-induced damage to DNA in normal fetal lung fibroblasts (MRC5). All three compounds demonstrate a concentration dependent reduction maximum with a pro-oxidant effect at higher (though not cytotoxic) concentrations. Manipulation of a simple 4-step reaction mechanism for free radical (FR) scavenging by AOs produced rate constant ratios which allowed the relative effectiveness (Q > EGCG > NAC) of the AOs to be evaluated.