The electronic structures of [Fe(Por)(Im)O] 1+ and [Fe(Por)(Im)O] (model compounds I and II, respectively) have been studied on the basis of density functional theory or DFT (Por ) porphine, Im ) imidazole). The a 2u π-cation radical state ( 4 A 2u ) was determined to be the ground state of compound I with total spin equal to 3 / 2 , while the a 1u π-cation state ( 4 A 1u ) was found to be 0.15 eV higher in energy than the 4 A 2u state. Since, in both states, the spins were localized to the porphyrin ring (S ) 1 / 2 ) and the Fe-O center (S ) 1), the magnetic coupling interaction between the two spin sites was examined by using a broken symmetry method. The calculated J value revealed very weak magnetic coupling for the A 2u state, which corresponded to the experimental data. The calculated J value revealed strong antiferromagnetic coupling for the A 1u state. The calculated Mössbauer spectrum parameters (quadrupole splitting and asymmetry) were similar for both the A 1u and A 2u states, and both agreed well with experimental values. On the other hand, the calculated hyperfine coupling constants for the nitrogen and the proton of the porphyrin ring were different in the two states. Although the experimental coupling constant values of the pyrrole nitrogen atoms were intermediate between the calculated values for the A 2u and A 1u states, the experimental values for the meso protons were closer to the values calculated for the A 2u state. These results suggest that the electronic structure of compound I is closer to the A 2u state than to the A 1u state. However, these results also suggest that there is the possibility that the electronic structure of compound I is an admixture of the A 1u state and the A 2u state. The electronic structure of compound II was calculated and compared with the electronic structure of compound I. The energetics of the redox reaction between the two compounds is discussed.
Toremifene, a compound which differs from tamoxifen by the substitution of a chlorine atom for a hydrogen atom in the ethyl group, is significantly less potent than tamoxifen in causing DNA adduct formation in rats. To examine the relationship of the DNA adduct-forming ability of these compounds with their physicochemical properties such as stable conformation and chemical reactivity, we carried out molecular mechanics, molecular dynamics, and quantum mechanics calculations for the two compounds. For tamoxifen, six stable conformers were identified by conformational search with CFF91 force field. Molecular dynamics simulations showed that these were often interconverted within 1.0 ns. On the other hand, although the conformation of stable conformers and dynamical behavior of toremifene were almost the same as those of tamoxifen, a few conformations were slightly different from those of tamoxifen owing to the effect of the chlorine atom at chloroethyl group. In addition, the stability of the allylic carbocation, which had been proposed as the reactive intermediate leading to DNA adduct formation, was calculated with both semiempirical and density functional methods. Results showed that the carbocation intermediate of toremifene was less stable than that of tamoxifen by 4-5 kcal/mol, suggesting that toremifene was less frequently activated to the intermediate than tamoxifen. Furthermore, the carbocation intermediates of two other tamoxifen derivatives, 4-iodotamoxifen and droxifene, which show no DNA adduct-forming ability, were also less stable compared with that of tamoxifen. These calculated results suggest a close relation between the stability of the proposed carbocation intermediate and DNA adduct-forming ability.
Pepleomycin (PEP), 3-[(S)-l'-phenylethylamino]propylaminobleomycinhas potent activity and is less pulmonary toxic than bleomycin (BLM). Biological activity and toxicity of the following degradation products of PEP have been studied in detail: the product of carbamoyl migration (ISO), the product of decarbamylation (DC), the product of ring closure of the side chain on the pyrimidine moiety (RC), the depyruvamide product (DP) and the product of an er zymatic inactivation (DA).These degradation products showed much lower activity than PEP it: vitro: antimicrobial and anti-HeLa activities, inhibition of DNA synthesis in AH66 cells and the DNA strand cleavage. Acute toxicity and pulmonary toxicity were tested in mice. Results indicated much lower acute toxicity corresponding to the decreased in vitro activity when compared to PEP. DP and RC did not cause lung fibrosis in mice, while ISO and DC showed 1/2.6 and 1/5.7 degree of pulmonary toxicity, respectively, in comparison with PEP. Pepleomycin (PEP: 3-[(S)-I'-phenylethylamino]propylaminobleomycin)"has been developed as a novel aialog of bleomycin (BLM) which has less pulmonary toxicity than BLM mixture clinically in use tocay in the treatment of cancer.Although PEP is very stable at room temperatures, several degradation products were detected in its heated aqueous solutions of about pH 6. They were confirmed to be due to the carbamoyl migration-) (ISO), decarbamylation'' (DC), depyruvamide formation') (DP) and ring closure of the side chain on the pyrimidine moiety',") (RC). BLM is inactivated to the deamido compound (DA) by BLM hydrolases'. Since there are no systematic informations of biological and toxicological properties of the degraded BLM, such studies seem to be important from the drug-safety aspect.Studies on the action mechanism of BLM have revealed the complex formation between BLM and Fe (II) fo lowed by the coordination of oxygen to it in the action of BLM against DNA 7,8). The most probable structure of the complex has been proposed on the basis of the structure of BLMS). The a-amino and the secondary /3-amino groups of the /J-aminoalanine moiety (V), the pyrimidine ring N-I, the imidazole ring N of the /3-hydroxyhistidine moiety (IV) and the amino group of IV are involved in the complex formation to produce a square pyramidal coordination.The first group occupies the apical position. The carbamoyl group has been suggested to be in the vacant 6th coordination site. The a-amino group of V is absent in DP and blocked and restrained by the intramolecular amide bonding in RC. The carbamoyl group is absent in DC, and that in ISO is not involved in coordination. In DA, the free carboxyl group of V may be involved in coordination instead of the a-amino group. All these degradation products have a weaker ability in the complex
Slice culture combined with the use of fluorescent dyes and/or the introduction of fluorescent protein genes provides live and three‐dimensional information on cytogenetic and histogenetic events at the level of the individual cell. Using slices prepared from midembryonic mouse cerebral wall tissue upon which fine DiI crystals were placed on the pial or ventricular surface, we recently found that dividing progenitor cells do not lose their pia‐connected (basal) processes and that the processes are inherited by daughter cells, including neurons (Miyata et al. [2001] Neuron 31:727–741). To understand more fully the biological significance of this inheritance process, the fate of each daughter cell should be monitored over a culture period extended long enough to allow a neuron to migrate up to the cortex or for a progenitor to proceed to the next round of division. Exposure of slices to 40%, instead of 20%, O2 significantly improved their overall thickening, cell production, and layer formation and also provided better spatial resolution by preventing the loss of transparency that accompanies cell death. © 2002 Wiley‐Liss, Inc.
An all-atom molecular dynamics simulation of a spherical micelle composed of amphiphilic N-acetylated poly(ethylene glycol)-poly(gamma-benzyl L-glutamate) (PEG-PBLG-Ac) block copolymers was performed in aqueous solution at 298.15 K and 1 atm. Such copolymers have received considerable attention as carriers in drug delivery systems. In this study, we used copolymers consisting of 11 EG units and 9 BLG units as models. Starting from the copolymers arranged spherically, the calculation predicted an equilibrium state consisting of a slightly elliptical micelle structure with a hydrophobic PBLG inner core and a hydrophilic PEG outer shell. The micelle structure was dynamically stable during the simulation, with the PEG blocks showing a compact helical conformation and the PBLG blocks an alpha-helix form. Multiple hydrogen bonds with solvent water molecules stabilized the helical conformation of the PEG blocks, leading to their hydration as shown by longer residence times of water molecules near the PEG ether oxygen atoms compared with that of bulk water. Some water molecules have also been found distributed within the hydrophobic core; they showed continuous exchange with bulk water during the simulation. Those molecules existed mostly as a cluster in spaces between the copolymers, forming hydrogen bonds among themselves as well as with the hydrophobic core through hydrophilic groups such as esters and amides. The water molecules forming hydrogen bonds with the micelle may play an important role in the stabilization of the micelle structure.
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