Conformational distortions

Large annulenes tend to undergo conformational distortion, cis-trans isomerizations, and sig-matropic rearrangements (p. 40 and p. 100). Methylene-bridged conjugated (4n + 2)-ic cyclopolyenes were synthesized with the expectation that these almost planar annulenes should represent stable HOckel arenes (E, Vogel, 1970, 1975). 

The tveak and reversible binding of these complexes to calf-thymus DNA (ct DNA) suggests a dominant electrostatic mode of interaction nevertheless, relevant conformational distortions of the double helix are caused [50]. A multinuclear NMR study of the reactivity of [Au(en)Cl2]Cl and [Au(en)2]Cl3 vith guanosine 5 -monopho-sphate (5 -GMP) reveals that in an aqueous solution only [Au(en)Cl2]Cl binds very weakly to 5 -GMP via N(7) to give a 1 1 adduct [48]. 

The structural and chemical mechanisms used by enzymes to achieve transition state stabilization have been reviewed in detail elsewhere (e.g., see Jencks, 1969, Warshel, 1998, Cannon and Benkovic, 1998, Copeland, 2000, Copeland and Anderson, 2002 and Kraut et al., 2003). Four of the most common strategies used by enzymes for transition state stabilization—approximation, covalent catalysis, acid/base catalysis, and conformational distortion—are discussed below. 

The conformational distortions that attend transition state formation involve both steric and electronic changes to the active site structure of the enzyme. These changes can include changes in steric packing forces, van der Waals interactions,... 

Further experiments focused therefore on [RuCl(en)(r 6-tha)]+ (12) and [RuCl(rj6-p-cym)(en)]+ (22), which represent the two different classes, and their conformational distortion of short oligonucleotide duplexes. Chemical probes demonstrated that the induced distortion extended over at least seven base pairs for [RuCl(rj6-p-cym)(en)]+ (22), whereas the distortion was less extensive for [RuCl(en)(rj6-tha)]+ (12). Isothermal titration calorimetry also showed that the thermodynamic destabilization of the duplex was more pronounced for [RuCl(r 6-p-cym)(en)]+ (22) (89). DNA polymerization was markedly more strongly inhibited by the monofunctional Ru(II) adducts than by monofunctional Pt(II) compounds. The lack of recognition of the DNA monofunctional adducts by HMGB1, an interaction that shields cisplatin-DNA adducts from repair, points to a different mechanism of antitumor activity for the ruthenium-arenes. DNA repair activity by a repair-proficient HeLa cell-free extract (CFE) showed a considerably lower level of damage-induced DNA repair synthesis (about six times) for [RuCl(en)(rj6-tha)] + compared to cisplatin. This enhanced persistence of the adduct is consistent with the higher cytotoxicity of this compound (89). 

For the a-SCS(OH) values in cyclohexanol derivatives Wray (406) has suggested that a further parameter is necessary to account for four-bond interactions, as indicated in 298 and 299. He remarked that significant deviations from the experimental chemical shifts indicate conformational distortion of the parent compound, and that such SCS values cannot be calculated for five-membered ring alcohols (406). 

A compound that binds at a different site to the natural receptor and produces a conformational distortion that prevents receptor activation. 

The different 3D-shapes adopted by aminoglycosides in the RNA- and enzyme-bound states suggest a possible structure-based chemical strategy to obtain antibiotics with better activity against resistant bacteria. Assiun-ing that, in these cases, some degree of conformational distortion of the substrates is required for enzymatic activity, it should be possible to design a conformationally locked oHgosaccharide that still retains antibiotic activity, but that is not susceptible to enzymatic inactivation (Fig. 8) [41]. 

E and F were then added to the substrate they formed hydrogen bonds without distorting their rings. However, E cannot form an intrachain hydrogen-bond to D because of the conformational distortion of the latter. 

A distinction is made between dispersion stability and chemical bond stability the former refers to the tenacity of a reversible tertiary structure in its dispersion medium (solid, liquid, or gas) wherein any conformational shift is theoretically transient and finite, albeit in a possibly long interval. Chemical instability involves decomposition of the primary structure of covalently linked glycosides. Chemical bond rupture is irreversible and the decomposition Ea is much higher than the Ea of conformational distortions and viscous flow. 

DNA adducts comprise nucleotides where chemical mutagenic substances are covalently bound. The common property of the chemical mutagenic substances is their electrophilic nature. Electrophilic sites (electron deficiency) bind to the nucleophilic sites of DNA or the proteins inducing covalent bonding leading to adduct formation, resulting in DNA conformation distortion, and replication and transcription blockage (Esaka etal. 2003). 

Co-C bond weakening and homolysis is induced by interaction of the coenzyme with the enzyme (e.g., through frans-axial ligand substitution or conformational distortion of the corrin ring). 

Thus a plot of E x versus l/n is linear for oligomeric substrands of known conducting polymers and should extrapolate to Emax = 0 for the perfectly degenerate, conjugated, infinite, linear, and "metallic" polymer. For instance, Ej, = 0 for graphite and for (SN)Y. For all other conducting polymers, this zero is not reached, because the polymer has finite strand length or because of conformational distortions or other defects. 

It is a major challenge to elucidate the mechanisms responsible for the efficiencies of enzymes. Jencks (1) offered the following classification of the mechanisms by which enzymes achieve transition state stabilization and the resulting acceleration of the reactions proximity and orientation effects of reactants, covalent catalysis, general acid-base catalysis, conformational distortion of the reactants, and preorganization of the active sites for transition state complementarity. 

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