The Reductive Deglycosylation Of Adriamycin In Aqueous Medium: A Pulse Radiolysis Study

The free radical (II) produced by one-electron reduction of adriamycin (I) exists in aqueous solution at pH 7.0 in equilibrium with the parent and the two-electron reduced form (III). Over some hundreds of milliseconds deglycosylation takes place yielding an aglycone (IV) which subsequently rearranges to form a more stable aglycone. 7-deoxyadriamycinone (V). The changes in the optical absorption spectrum accompanying these processes are reported. The rate constant for III + IV is 1.1 s^-1 and for IV + V is 1.5 × 10^--² s.^-1. At pH 4.0 the two electron reduced form of adriamycin exists predominantly in a different tautomeric form (VII). It is suggested that this deglycosylates via a free radical mechanism involving the acidic form of the semiquinone free radical (VI)     

Quantum chemical study of the structure and properties of citrinin

Detailed structures and electronic properties of three tautomeric forms of the toxin citrinin were investigated using several quantum calculation methods. Energetic preference of the predominant p- and o-quinone methide tautomeric forms is dependent on the method of calculation. A previously unstudied carboxylic acid enol tautomer was calculated to be surprisingly stable in vacuo, being within 2.5 kcal mol^? 1 at the B3LYP/6-311++G(2d,2p) level of theory. Despite differences in bond nature and connectivity of tautomers, the natural bond orbital analysis revealed that tautomeric forms share similar natural charges and natural electron configurations. Calculated bond lengths corresponded with experimentally observed values and assignments for the calculated infrared vibrational frequencies are reported.     

Proton transport in carbonic anhydrase: Insights from molecular simulation

This article reviews the insights gained from molecular simulations of human carbonic anhydrase II (HCA II) utilizing non-reactive and reactive force fields. The simulations with a reactive force field explore protein transfer and transport via Grotthuss shuttling, while the non-reactive simulations probe the larger conformational dynamics that underpin the various contributions to the rate-limiting proton transfer event. Specific attention is given to the orientational stability of the His64 group and the characteristics of the active site water cluster, in an effort to determine both of their impact on the maximal catalytic rate. The explicit proton transfer and transport events are described by the multistate empirical valence bond (MS-EVB) method, as are alternative pathways for the excess proton charge defect to enter/leave the active site. The simulation results are interpreted in light of experimental results on the wild-type enzyme and various site-specific mutations of HCA II in order to better elucidate the key factors that contribute to its exceptional efficiency.     

Cerium(IV)-mediated oxidation of flavonol with relevance to flavonol 2,4-dioxygenase. Direct evidence for spin delocalization in the flavonoxy radical

The cerium(IV)-mediated oxidation of 3-hydroxy-4'-methylflavone (1) proceeds by H-atom abstraction forming the flavonoxy radical (7), and the subsequent combination of its resonance forms leads to the 3-hydroxy-4'-methylflavone dehydro dimer (9). The above system serves as direct evidence for the intermediacy of the flavonoxy radical, its spin delocalization, and also indirect evidence for valence tautomerism as a key step on the substrate activation both in the quercetinase and its biomimic model system.     

A study in scarlet: enzymes of ketocarotenoid biosynthesis in the flowers of Adonis aestivalis

The red ketocarotenoid astaxanthin (3,3'-dihydroxy-4,4'-diketo-beta,beta-carotene) is widely used as an additive in feed for the pigmentation of fish and crustaceans and is frequently included in human nutritional supplements as well. There is considerable interest in developing a plant-based biological production process for this valuable carotenoid. Adonis aestivalis (Ranunculaceae) is unusual among plants in synthesizing and accumulating large amounts of astaxanthin and other ketocarotenoids. The formation of astaxanthin requires only the addition of a carbonyl at the number 4 carbon of each beta-ring of zeaxanthin (3,3'-dihydroxy-beta,beta-carotene), a carotenoid typically present in the green tissues of higher plants. We screened an A. aestivalis flower library to identify cDNAs that might encode the enzyme that catalyzes the addition of the carbonyls. Two closely related cDNAs selected in this screen were found to specify polypeptides similar in sequence to plant beta-carotene 3-hydroxylases, enzymes that convert beta-carotene (beta,beta-carotene) into zeaxanthin. The Adonis enzymes, however, exhibited neither 4-ketolase nor 3-hydroxylase activity when presented with beta-carotene as the substrate in Escherichia coli. Instead, the products of the Adonis cDNAs were found to modify beta-rings in two distinctly different ways: desaturation at the 3,4 position and hydroxylation of the number 4 carbon. The 4-hydroxylated carotenoids formed in E. coli were slowly metabolized to yield compounds with ketocarotenoid-like absorption spectra. It is proposed that a 3,4-desaturation subsequent to 4-hydroxylation of the beta-ring leads to the formation of a 4-keto-beta-ring via an indirect and unexpected route: a keto-enol tautomerization.     

Ab initio double-ζ (D95) valence bond calculations for the ground states of NO2, O3, and ClO2

The results of some double-ζ D95 valence-bond (VB) calculations are reported for the ground states of nitrogen dioxide, NO₂ (17 valence electrons), ozone, O₃ (18 valence electrons), and chlorine dioxide, ClO₂ (19 valence electrons). The Mulliken, Löwdin and Hiberty structural weights are reported for nine (NO₂), six (O₃), and three (ClO₂) Lewis structures that differ in the locations of the π electrons. The most important Lewis structures for NO₂ are the uncharged spin-paired diradical structure VII and the two equivalent structures that carry no formal charges (II and V). For O₃ and ClO₂, the primary Lewis structures are, respectively, the uncharged singlet diradical structure III, and I with the odd electron located in the chlorine 3pπ atomic orbital.For ClO₂, the results of some STO-6G calculations, with 16 canonical Lewis type structures included, give a much smaller value for the chlorine odd-electron charge than does the D95 vb2000 calculation with a Hartree-Fock core. However, the structural weights obtained from the STO-6G calculations do reflect the expectation that small atomic formal charge separations, together with some Cl-O covalent σ-bonding, are associated with large structural weights.     

Valence and anion binding of bovine ribonuclease A between pH 6 and 8

Several studies have shown that divalent anion binding to ribonuclease A (RNase A) contributes to RNase A folding and stability. However, there are conflicting reports about whether chloride binds to or stabilizes RNase A. Two broad-zone experimental approaches, membrane-confined electrophoresis and analytical ultracentrifugation, were used to examine the electrostatic and electrohydrodynamic characteristics of aqueous solutions of bovine RNase A in the presence of 100 mM KCl and 10 mM Bis-Tris propane over a pH range of 6.00-8.00. The results of data analysis using a Debye-Huckel-Henry model, compared with expectations based on pK(A) values, are consistent with the binding of two chlorides by RNase A. The decreased protein valence resulting from anion binding contributes 2-3 kJ/mol to protein stabilization. This work demonstrates the utility of first-principle valence determinations to detect protein solution properties that might otherwise remain undetected.     

Structural studies of lanthanide complexes with tetradentate nitrogen ligands

Complexes have been synthesised with bis(2-pyridine carboxaldehyde) ethylenediimine (1) and bis(2-pyridine carboxaldehyde)propylene-1,3-diimine (2) with all of the available lanthanide trinitrates. Crystal structures were obtained for all but one complex with 1 and for all but one complex with 2. Four distinct structural types were established for 1 but only two for 2, although in all cases the structures contained one ligand bound to the metal in a tetradentate fashion. With 1, the four different structures of the lanthanide(III) nitrate complexes included 11-coordinate [Ln(1)(NO₃)₃(H₂O)] for Ln = La; 10 coordinate [Ln(1)(NO₃)₃(H₂O)] with one monodentate and two bidentate nitrates for Ln = Ce, then 10-coordinate [Ln(1)(NO₃)₃] for Ln = Pr-Yb with three bidentate nitrates; and 9-coordinate [Ln(1)(NO₃)₃] with one monodentate and two bidentate nitrates for Ln = Lu. On the other hand for 2 only two distinct types of structure are obtained, the first type with Ln = La-Pr and the second type for Ln = Sm-Lu, although all are 10-coordinate with stoichiometry [Ln(2)(NO₃)₃]. The difference between the two types is in the disposition of the ligand relative to the nitrates. With the larger lanthanides La-Pr the ligand is found on one side of the coordination sphere with the three nitrate anions on the other. In these structures, the ligand is folded such that the angle between the two pyridine rings approaches 90°, while with the smaller lanthanides Sm-Lu, two nitrates are found on one side of the ligand and one nitrate on the other and the ligand is in an extended conformation such that the two pyridine rings are close to being coplanar. In both series of structures, the Ln-N and Ln-O bond lengths were consistent with the lanthanide contraction though there are significant variations between ostensibly equivalent bonds which are indicative of intramolecular hydrogen bonding and steric crowding in the complexes.     

Formation of stable and metastable porphyrin- and corrole-iron(IV) complexes and isomerizations to iron(III) macrocycle radical cations

Oxidations of three porphyrin-iron(III) complexes (1) with ferric perchlorate, Fe(ClO₄)₃, in acetonitrile solutions at −40 °C gave metastable porphyrin-iron(IV) diperchlorate complexes (2) that isomerized to known iron(III) diperchlorate porphyrin radical cations (3) when the solutions were warmed to room temperature. The 5,10,15,20-tetraphenylporphyrin (TPP), 5,10,15,20-tetramesitylporphyrin (TMP), and 2,3,7,8,12,13,17,18-octaethylporphyrin (OEP) systems were studied by UV-visible spectroscopy. Low temperature NMR spectroscopy and effective magnetic moment measurements were possible with the TPP and TMP iron(IV) complexes. Reactions of two corrole systems, 5,10,15-tris(pentafluorophenyl)corrole (TPFC) and 5,15-bis(pentafluorophenyl)-10-p-methoxyphenylcorrole (BPFMC), also were studied. The corrole-iron(IV) chlorides reacted with silver salts to give corrole-iron(IV) complexes. The corrole-iron(IV) nitrate complexes were stable at room temperature. (TPFC)-iron(IV) toslyate, (TPFC)-iron(IV) chlorate, and (BPFMC)-iron(IV) chlorate were metastable and rearranged to their electronic isomers iron(III) corrole radical cations at room temperature. (TPFC)-iron(III) perchlorate corrole radical cation was the only product observed from reaction of the corrole-iron(IV) chloride with silver perchlorate. For the metastable iron(IV) species, the rates of isomerizations to the iron(III) macrocycle radical cation electronic isomers in dilute acetonitrile solutions were relatively insensitive to electron demands of the macrocyclic ligand but reflected the binding strength of the ligand to iron. Kinetic studies at varying temperatures and concentrations indicated that the mechanisms of the isomerization reactions are complex, involving mixed order reactivity.     

Exploring the interactional details between aldose reductase (AKR1B1) and 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid through molecular dynamics simulations

Aldose reductase (AKR1B1) has been considered as a significant target for designing drugs to counteract the development of diabetic complications. In the present study, molecular dynamics (MD) simulations and molecular mechanics generalized Born surface area (MM-GB/SA) calculations were performed to make sure which tautomer is the preferred one among three tautomeric forms (Mtia1, Mtia2, and Mtia3) of 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (Mtia) for binding to AKR1B1. The overall structural features and the results of calculated binding free energies indicate that Mtia1 and Mtia2 have more superiority than Mtia3 in terms of binding to AKR1B1. Furtherly, the local active site conformational characteristics and non-covalent interaction analysis were identified. The results indicate that the combination of Mtia2 and AKR1B1 is more stable than that of Mtia1. Furthermore, two extra hydrogen bonds between AKR1B1 and Mtia2 are found with respect to Mtia1. In addition, Mtia2 makes slightly stronger electrostatic interaction with the positively charged nicotinamide group of NADP⁺ than Mtia1. Based on the results above, Mtia2 is the preferred tautomeric form among the three tautomers. Our study can provide an insight into the details of the interaction between AKR1B1 and Mtia at the atomic level, and will be helpful for the further design of AKR1B1 inhibitors.