Volume 76, Issue 2

Toxic reactants are a common result of the interaction of sunlight with pharmaceutical agents transported in the blood system or applied topically. Over the past decade there has been a considerable amount of research toward understanding both the unimolecular deactivation pathway of photoexcited pharmaceutical products and their photosensitizing capability in the presence of biological substrates. This work summarizes recent developments in the study of the photodegradation mechanism of ketoprofen, fenofibric acid, and tiaprofenic acid. An analysis of excited-state electronic energy levels, the type of intermediates formed following excitation, and transient intermediate lifetimes is presented. The analysis involves both parent drugs and their major photoproducts. Phototoxicity, usually the result of adverse photochemical reactions following direct photoexcitation of the drugs, is shown to be strongly related to the photoexcitation of photoproducts when high radiation dose conditions prevail. The photoproducts are the species directly involved in photosensitizing reactions.

Several advances in the coordination chemistry of stable free-radical species over the past six years are documented in this review article. Specifically, a number of recent reports focused on the coordination chemistry of chelating nitroxide ligands are highlighted, with an emphasis on enhanced magnetic or optical properties in these complexes. Furthermore, very intriguing recent magnetic and optical studies with one-dimensional nitroxide chain complexes (new "Glauber" chains and chiral magnets) are also discussed. The verdazyls are another family of stable radicals whose coordination chemistry was literally unexplored prior to 1997. A summary of recent reports discussing metal-verdazyl coordination complexes is also presented, followed by an eye to the future of stable radical design and the coordination chemistry of these interesting molecules.

Computer simulation methods spanning several temporal and spatial scales are reviewed, focusing on their applications on the neuromuscular synapse. Quantum mechanics treats the enzymatic catalysis of neurotransmitters on the picometer scale. Molecular dynamics reveals conformational changes of the enzyme acetylcholinesterase for nanoseconds. Brownian dynamics follow the substrate molecule in its diffusion on the microsecond level. Methods such as finite elements describe the diffusion of neurotransmitters as a changing concentration continuum in the synapse. Promising directions for future research include integration of methods on several scales, and applying these methods to the acetylcholine receptor.

Cytochrome c oxidase (CcO) is an enzyme that catalyzes efficient, selective, and fast reduction of molecular oxygen to water as a means of respiratory energy generation. The biomimetic approach provides a valuable alternative to traditional biochemical methods to unravel the structural and electronic properties of the CcO's catalytic (heme/Cu B ) site that endow the enzyme with its unique reactivity. However, the contribution of biomimetic studies of CcO to our understanding of CcO's biochemistry has been complicated by the lack of convincing evidence that the reactivity of the biomimetic analogs is relevant to that of CcO. Recently reported porphyrin-based compounds are the first analogs that reproduce key aspects of the reactivity of CcO toward O 2 . Extensive data collected with these biomimetic analogs demonstrate that the bimetallic nature of the CcO's catalytic site may be an adaptation to reduction of O 2 under turnover-limiting electron flux; a monometallic heme-only site appears sufficient for rapid O 2 reduction under physiologically relevant conditions of pH and electrochemical potential, provided that electron flow to the heme is not kinetically limited. These biomimetic data suggest that in CcO the distal Cu ion (Cu B ) may serve as an electron-preloading site to allow the enzyme to accumulate a sufficient number of external reducing equivalents before it even binds O 2 . This mechanism minimizes the population of enzymatic species containing partially reduced oxygen species.

The possibility of investigating copper proteins by nuclear magnetic resonance is here treated. It is shown that the solution structure and dynamic information can be obtained on Type I Cu(II) proteins, which have a relatively short electron relaxation time ( τ S = 10 -10 s). The experimental approach, in this case, is routine, although tailored for fast-relaxing nuclei. In the case of Type II Cu(II) proteins, when the electron relaxation times are larger ( τ S = 10 -8 - 10 -9 s) and proton linewidths are broadened beyond detectable limits, heteronuclear 13 C spectra with direct detection can be used and the solution structure can again be obtained. In this review, it is shown that Cu(II) proteins are now amenable for NMR investigation, the size being the only limit as in diamagnetic proteins.

Studies in this laboratory have been concerned with mapping the chemical properties and mechanisms of NO interactions with hemes and other metal centers. These are models relevant to the mammalian biology of nitric oxide, an important bioregulatory molecule. Presented here will be an overview of flash photolysis kinetics investigations of ferri- and ferro-heme nitrosyl formation in model complexes and several heme proteins. Also described will be ongoing studies of reductive nitrosylation mechanisms involving the reactions of NO with water-soluble Fe(III) porphyrins and ferri-heme proteins and of several Cu(II) model complexes.

In addition to the widely studied biometal complexes of tetrapyrrole ligands such as hemes (Fe), cobalamins (Co), and factor F430 (Ni), there are other, more recently established systems in which transition metals and redox-active cofactors such as pterins, flavins, quinones, or phenoxyl radicals cooperate in electron transfer and substrate activation. The cases of the molybdenum or tungsten containing oxotransferases involving pyranopterin as essential ligand and the copper-dependent quinoproteins such as amine oxidases will be discussed. The structural and functional description of these systems will be complemented by results from model studies.

This paper summarizes recent synthetic efforts devoted to the generation of new, second-generation texaphyrin-type drugs, specifically species that involve known or potential anticancer agents covalently attached to a tumor-localizing texaphyrin core. Particular emphasis will be placed on the strategies needed to prepare such systems, as well as on the choice of active group being subject to attachment.

Firstly, the self-stacking properties of ATP 4- and the effects of metal ions and protons on these properties are described. Some examples involving macrochelate formation between phosphate-coordinated metal ions (M 2+ ) and N7 of the adenine residue in MATP 2- are discussed, and this is followed by considerations on mixed ligand complexes consisting of ATP 4- , M 2+, and amino acid anions with side chains that allow either aromatic-ring stacking or hydrophobic interactions with the adenine moiety; this gives rise to selectivity. Next, the properties of diphosphorylated 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA 2- ; Adefovir), i.e., of PMEApp 4- , are compared with those of (2'-deoxy)ATP 4- with regard to their metal ion-binding qualities, and in this way it can be explained why PMEApp 2- is initially an excellent substrate for nucleic acid polymerases. Of course, after incorporation of the PMEA residue into the growing nucleic acid chain, this is terminated and this is how PMEA exerts its antiviral properties [its bis(pivaloyloxymethyl)ester, Adefovir dipivoxil , was recently approved for use in hepatitis B therapy]. Finally, the change in free energy connected with (macro)chelate formation or intramolecular stacking interactions and the effect of a reduced dielectric constant of the solvent on the stability of complexes and their structures in solution is considered.

Influences of the morphology on the thermal and mechanical properties of poly(α-methylstyrene- co -acrylonitrile)/poly[(methyl acrylate- co -methyl methacrylate)] (PαMSAN/PMMA) blends have been investigated. DSC measurements confirm that all blends were phase-separated due to the temperature at which they have been extruded and squeeze-molded. Based on the cloudpoints of 17 blends and TEM micrographs, the interaction parameters as a function of temperature and composition were calculated for the lower critical solution temperature (LCST) system. Varying the morphology by annealing without changing the composition of the system resulted in a finer morphology for the 85/15 blends, while the 40/60 blend showed an increase in the domain size with annealing time. Tensile strength and fracture toughness indicate that the PαMSAN domains in the tougher PMMA matrix cause a deterioration in the mechanical properties of the blends, while the PMMA domains in the PαMSAN matrix improve the mechanical properties. No clear conclusions on the influence of morphology on fracture toughness could be drawn because in one case (40/60 blend) the fracture toughness decreases slightly by annealing and in the other case (85/15 blend) fracture toughness values increase slightly with decreasing phase separation by annealing. In situ strained thin sections in the TEM indicated no effect of annealing on the micromechanical behavior. Shear deformation was observed as the prevailing deformation mechanism in the PαMSAN and fibrillized crazing in the PMMA-rich blends. From fatigue crack growth experiments it was concluded that the fatigue crack propagation threshold is higher for PMMA than for PαMSAN. Tests on the annealed samples of PαMSAN/PMMA 85/15 and 40/60 showed that the differences in morphology did not affect the fatigue crack growth resistance significantly. From the features of the fracture surface investigated by SEM, the conclusion can be drawn that the fatigue crack propagates faster in the more brittle PαMSAN phase, but the overall advance of the crack front is controlled at the interphases, resulting in a crack propagation gradient along the interphase.

This paper presents an overview of methods for chemical speciation analysis of elements in samples of sediments and soils. The sequential leaching procedure is thoroughly discussed, and examples of different applications are shown. Despite some drawbacks, the sequential extraction method can provide a valuable tool to distinguish among trace element fractions of different solubility related to mineralogical phases. The understanding of the speciation of trace elements in solid samples is still rather unsatisfactory because the appropriate techniques are only operationally defined. The essential importance of proper sampling protocols is highlighted, since the sampling error cannot be estimated and corrected by standards. The Community Bureau of Reference (BCR) protocols for sediment and soil give a good basis for most of the solid samples, and the results can be compared among different laboratories.

This paper presents terms and definitions for capillary electromigration techniques for separation, qualitative and quantitative analysis and physico-chemical characterization. Names and descriptions for such techniques (e.g., capillary electrophoresis and capillary electrochromatography) as well as terms for the phenomenon of electroosmotic flow are included.