Kinetic studies of the on/off reaction of the amino group in the side chain of Cu(II), Ni(II), and Co(II) complexes with 14-membered tetraazamacrocycles

The kinetics of the on/off reaction of the amino group in the side chain of tetraazamacrocyclic Cu2+, Ni2+ and Co2+ complexes has been measured. The rate law k(obs)=k(0)+k(H)[H+]+k(OH)/[H+], the sum of the forward and reverse reaction, gives rise to u-shaped pH dependences from which the three rate constants can be determined. k(H) describes the proton assisted dissociation of the amino group bound to the metal ion and is roughly correlated to the equilibrium constant of the reaction. k(OH) is determined by the protonation constant of the free amino group and the rate constant describing the binding of the amino group to the metal ion. k(0) is composed of the rate constant for the opening of the chelate ring without proton assistance and the rate for the reactivity of the ammonium group in the formation of the chelate ring. Our results show that the rates of the opening and closing of the chelate ring are very little dependent on the nature of the metal ion.     

Selective metal promoted hydrolysis of nitrile groups in the side chain of tetraazamacrocyclic Cu2+-complexes

The metal promoted hydrolysis of nitrile groups in the side chains of tetraazamacrocyclic Cu2+ complexes has been studied by stopped-flow techniques. It is shown that the reaction proceeds by an intramolecular attack of an axially coordinated OH- onto the nitrile group to give the corresponding amide. In alkaline solution the amide then deprotonates and binds to the axial position of the Cu2+ thus preventing further coordination of an OH-. This explains mechanistically that in the Cu2+ complexes of macrocycles carrying two nitrile functions only one is selectively hydrolysed. The nitrile hydrolysis has also been used on a preparative scale to synthesize tetraazamacrocycles with two different side chains. X-Ray diffractions of several products are presented to confirm the structures and the results from the kinetics and equilibria measurements.     

1,25-Dihydroxyvitamin D3 and analogues protect primary human keratinocytes against UVB-induced DNA damage

Exposure to UVB irradiation is a major risk factor for the development of skin cancer. Therefore, it is important to identify agents that can offer protection against UVB-caused damage. Photocarcinogenesis is caused largely by mutations at sites of incorrectly repaired DNA photoproducts, of which the most common are the cyclobutane pyrimidine dimers (CPDs). In this study, we demonstrated that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] protects primary human keratinocytes against the induction of CPDs by UVB. This protection required pharmacologic doses 1,25(OH)2D3 and an incubation period of at least 8 h before irradiation. Furthermore, we provided arguments indicating that the anti-proliferative capacity of 1,25(OH)2D3 underlies its protective effect against UVB-induced DNA damage. Finally, we showed that 19-nor-14-epi-23-yne-1,25(OH)2D3 (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)2D3 (TX 527), two low-calcemic analogues of 1,25(OH)2D3, were even 100 times more potent than the parent molecule in inhibiting UVB-caused DNA damage. These molecules are therefore promising candidates for the chemoprevention of UVB-induced skin cancer.     

Direct assignment of enantiofacial discrimination on single heterocyclic substrates by self-induced CD

The first direct assignment of highly dynamic enantiofacial discrimination acting on a single heterocyclic substrate has been achieved by a combination of experimental and theoretical CD spectroscopy. The interaction of chirally modified hosts based on triphenylene ketals with appropriate prochiral guests can lead to the preferential formation of one diastereomeric host-guest complex. This reversible stereoselective binding transmits the chiral information from remote chiral groups in the host to the strongly absorbing triphenylene chromophore, which gives rise to self-induced CD. This effect was exploited for the determination of the enantiofacial recognition in various host-guest systems. Inversion of the steric demand either of the chiral substituents at the host or of the prochiral guest leads to almost complete inversion of the resulting CD spectra. For the assignment of the absolute stereochemistry of the complexes, a combined molecular dynamics/quantum-chemical approach was successfully employed. Despite the size and the highly dynamic character of the supramolecular systems, fundamental properties of the systems and details of the spectra were simulated accurately, providing access to fast and reliable assignment of the enantiofacial preference. The results are highly consistent with available X-ray data.     

Kinetic and mechanistic studies on the reaction of nitric oxide with a water-soluble octa-anionic iron(III) porphyrin complex

The polyanionic water-soluble and non-mu-oxo-dimer-forming iron porphyrin iron(III) 5(4),10(4),15(4),20(4)-tetra-tert-butyl-5(2),5(6),15(2),15(6)-tetrakis[2,2-bis(carboxylato)ethyl]-5,10,15,20-tetraphenylporphyrin, (P(8-))Fe(III) (1), was synthesized as an octasodium salt by applying well-established porphyrin and organic chemistry procedures to bromomethylated precursor porphyrins and characterized by standard techniques such as UV-vis and (1)H NMR spectroscopy. A single pK(a1) value of 9.26 was determined for the deprotonation of coordinated water in (P(8-))Fe(III)(H(2)O)(2) (1-H(2)()O) present in aqueous solution at pH <9. The porphyrin complex reversibly binds NO in aqueous solution to give the mononitrosyl adduct, (P(8-))Fe(II)(NO(+))(L), where L = H(2)O or OH(-). The kinetics of the binding and release of NO was studied as a function of pH, temperature, and pressure by stopped-flow and laser flash photolysis techniques. The diaqua-ligated form of the porphyrin complex binds and releases NO according to a dissociative interchange mechanism based on the positive values of the activation parameters DeltaS() and DeltaV() for the "on" and "off" reactions. The rate constant k(on) = 6.2 x 10(4) M(-1) s(-1) (24 degrees C), determined for NO binding to the monohydroxo-ligated (P(8-))Fe(III)(OH) (1-OH) present in solution at pH >9, is markedly lower than the corresponding value measured for 1-H(2)O at lower pH (k(on) = 8.2 x 10(5) M(-1) s(-1), 24 degrees C, pH 7). The observed decrease in the reactivity is contradictory to that expected for the diaqua- and monohydroxo-ligated forms of the iron(III) complex and is accounted for in terms of a mechanistic changeover observed for 1-H(2)O and 1-OH in their reactions with NO. The mechanistic interpretation offered is further substantiated by the results of water-exchange studies performed on the polyanionic porphyrin complex as a function of pH, temperature, and pressure.     

Eine lokale Charakterisierung der Veronesemannigfaltigkeiten

We show that the Veronese submanifold of the standard sphere may be characterised by the property that the second fundamental form is-up to a constant factor-an isometric map from the symmetric product of the tangent space onto the normal space.