Light-switchable diazocines as potential inhibitors of testosterone-synthesizing 17ß-hydroxysteroid dehydrogenase 3.

In patients with prostate carcinoma as well as in some other cancer types, the reduction of testosterone levels is desired because the hormone stimulates cancer cell growth. One molecular target for this goal is the inhibition of 17ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3), which produces testosterone from its direct precursor androstenedione. Recent research in this field is trying to harness photopharmacological properties of certain compounds so that the inhibitory effect could be turned on and off by irradiation. Seven new light-switchable diazocines were investigated with regard to their inhibition of 17ßHSD3. For this purpose, transfected HEK-293 cells and isolated microsomes were treated with the substrate and the potential inhibitors with and without irradiation for an incubation period of 3 or 5 h. The amount of generated testosterone was measured by UHPLC and compared between samples and control as well as between irradiated and non-irradiated samples. There was no significant difference between samples with and without irradiation. However, four of the seven diazocines led to a significantly lower testosterone production both in cell and in microsome assays. In some of the irradiated samples, a partial destruction of the diazocines was observed, indicated by an additional UHPLC peak. However, the influence on the inhibition is negligible, because the majority of the substance remained intact. In conclusion, new inhibitors of 17ßHSD3 have been found, but so far without the feature of a light switch, since the configurational alteration of the diazocines by irradiation did not lead to a change in bioactivity. Further modification might help to find a light-switching molecule that inhibits only in one configuration.

Reduction of photoswitched, nitrogen bridged N-acetyl diazocines limits inhibition of 17ßHSD3 activity in transfected human embryonic kidney 293 cells.

Testosterone depletion is a common aim in the treatment of hormone-dependent prostate cancer, since the steroid boosts the tumor's proliferation. Therefore, inhibition of 17ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3), which catalyzes the carbonyl reduction of androstenedione to testosterone, represents an expedient therapeutic drug target. Among the compounds targeting 17ßHSD3, tetrahydrodibenzazocines have been reported to be highly potent inhibitors. Thus, we hypothesized that structural analogs to the tetrahydrodibenzazocine scaffold, namely diazocines, which contain an azo group instead of the ethylene moiety, are also able to inhibit 17ßHSD3. Diazocines consist of a photoresponsive core and can be isomerized from Z into E configuration by irradiation with a specific wavelength. In the present study, 17ßHSD3 inhibition by diazocine photoisomers was examined in transfected human embryonic kidney 293 cells (HEK-293) and isolated microsomes. For this purpose, cells or microsomes were treated with androstenedione and incubated for 2 or 24 h in the presence or absence of irradiated and non-irradiated diazocines. Testosterone formation was determined by uHPLC. We report a weak inhibition of 17ßHSD3 activity by diazocines in HEK-293 cells and microsomes. Furthermore, we found no significant difference between samples treated with irradiated and non-irradiated diazocines in terms of inhibition. However, we detected a new compound by HPLC analysis, which only appeared in light-treated samples, indicating a chemical modification of the photoswitched diazocines, presumably rendering them ineffective. Further investigations revealed that this modification occurs in the presence of reducing agents like dithiothreitol and glutathione. A preliminary mass-spectrometric analysis suggests that the N-N double bond is reduced, resulting in a dianiline derivative. Nevertheless, optimized photoswitchable diazocine derivatives, which are stable in a cellular environment, might serve as potent 17ßHSD3 inhibitors, effective only in irradiated tissue.

Synthesis of Functionalized Perfluorinated Porphyrins for Improved Spin Switching.

We have established a method to synthesize perfluorinated meso-phenylporphyrins with one phenyl group bearing a substituent in the ortho position. These novel electron-deficient porphyrins are interesting for model enzymes, catalysis, photodynamic therapy, and electron transfer. The key step is the synthesis of an iodine-substituted porphyrin and its Suzuki cross coupling with boronic acid derivatives. We applied the novel strategy to synthesize a highly electron-deficient, azopyridine-substituted Ni-porphyrin that undergoes an improved ligand-driven coordination-induced spin-state switch.

UV/Vis Spectroscopy Studies of the Photoisomerization Kinetics in Self-Assembled Azobenzene-Containing Adlayers.

Direct comparative studies of the photoisomerization of azobenzene derivatives in self-assembled adlayers on Au and as free molecules in dichloromethane solution were performed using UV/vis spectroscopy. For all studied systems a highly reversible trans-cis isomerization in the adlayer is observed. Quantitative studies of the absorbance changes and photoisomerization kinetics reveal that in azobenzenes mounted as freestanding vertical groups on the surface via triazatriangulene-based molecular platforms photoswitching is nearly uninhibited by the local environment in the adlayer. The blue-shift of the π-π* transition in adlayers of these molecules is in good agreement with theoretical studies of the effect of excitonic coupling between the molecules. In contrast, in azobenzene-containing thiol self-assembled monolayers the fraction of photoswitching molecules and the photoisomerization kinetics are significantly reduced compared to free molecules in solution.

Rational design of a room temperature molecular spin switch. The light-driven coordination induced spin state switch (LD-CISSS) approach.

Extensive use of quantum chemical calculations has been made to rationally design a molecule whose spin state can be switched reversibly using light of two different wavelengths at room temperature in solution. Spin change is induced by changing the coordination number of a nickel complex. The coordination number in turn is switched using a photochromic ligand that binds in one configuration and dissociates in the other. We demonstrate that successful design relies on a precise geometry fit and delicate electronic tuning. Our designer complex exhibits an extremely high long-term switching stability (more than 20 000 cycles) and a high switching efficiency. The high-spin state is extraordinarily stable with a half-life of 400 days at room temperature. Switching between the dia- and paramagnetic state is achieved with visible light (500 and 430 nm). The compound can also be used as a molecular logic gate with light and pH as input and the magnetic state as non-destructive read-out.

The growth and electronic structure of azobenzene-based functional molecules on layered crystals.

In situ ultraviolet photoelectron spectroscopy is used to study the growth of ultrathin films of azobenzene-based functional molecules (azobenzene, Disperse Orange 3 and a triazatriangulenium platform with an attached functional azo-group) on the layered metal TiTe(2) and on the layered semiconductor HfS(2) at liquid nitrogen temperatures. Effects of intermolecular interactions, of the substrate electronic structure, and of the thermal energy of the sublimated molecules on the growth process and on the adsorbate electronic structure are identified and discussed. A weak adsorbate-substrate interaction is particularly observed for the layered semiconducting substrate, holding the promise of efficient molecular photoswitching.

Magnetic bistability of molecules in homogeneous solution at room temperature.

Magnetic bistability, as manifested in the magnetization of ferromagnetic materials or spin crossover in transition metal complexes, has essentially been restricted to either bulk materials or to very low temperatures. We now present a molecular spin switch that is bistable at room temperature in homogeneous solution. Irradiation of a carefully designed nickel complex with blue-green light (500 nanometers) induces coordination of a tethered pyridine ligand and concomitant electronic rearrangement from a diamagnetic to a paramagnetic state in up to 75% of the ensemble. The process is fully reversible on irradiation with violet-blue light (435 nanometers). No fatigue or degradation is observed after several thousand cycles at room temperature under air. Preliminary data show promise for applications in magnetic resonance imaging.

Transplantation outcomes in primary hyperoxaluria.

Optimal transplantation strategies are uncertain in primary hyperoxaluria (PH) due to potential for recurrent oxalosis. Outcomes of different transplantation approaches were compared using life-table methods to determine kidney graft survival among 203 patients in the International Primary Hyperoxaluria Registry. From 1976-2009, 84 kidney alone (K) and combined kidney and liver (K + L) transplants were performed in 58 patients. Among 58 first kidney transplants (32 K, 26 K + L), 1-, 3- and 5-year kidney graft survival was 82%, 68% and 49%. Renal graft loss occurred in 26 first transplants due to oxalosis in ten, chronic allograft nephropathy in six, rejection in five and other causes in five. Delay in PH diagnosis until after transplant favored early graft loss (p = 0.07). K + L had better kidney graft outcomes than K with death-censored graft survival 95% versus 56% at 3 years (p = 0.011). Among 29 year 2000-09 first transplants (24 K + L), 84% were functioning at 3 years compared to 55% of earlier transplants (p = 0.05). At 6.8 years after transplantation, 46 of 58 patients are living (43 with functioning grafts). Outcomes of transplantation in PH have improved over time, with recent K + L transplantation highly successful. Recurrent oxalosis accounted for a minority of kidney graft losses.

Femtosecond fluorescence up-conversion spectroscopy of a rotation-restricted azobenzene after excitation to the S1 state.

Femtosecond time-resolved fluorescence up-conversion spectroscopy has been used in a study of the photoinduced isomerization reactions of a rotation-restricted trans-azobenzene (trans-AB) derivative capped by a crown ether (1), a chemically similar open derivative (2), and unsubstituted trans-AB (3) after excitation to the S1 (npi*) state at lamda=475 nm in dioxane solution. The observed biexponential temporal fluorescence profiles for 1 and 2 were almost indistinguishable within experimental error. The fitted fast fluorescence decay times (+/-2sigma) for the two compounds were tau1 (1) = (0.79 +/- 0.20) and tau1 (2) = (1.05 +/- 0.20) ps, compared to tau1 (3) = (0.37 +/- 0.06) ps. The second decay components could be described with tau2 (1) = (20.3 +/- 9.5) resp. tau2 (2) = (19.0 +/- 6.0) ps, vs. tau2 (3) = (3.26 +/- 0.85) ps. The very similar lifetimes strongly suggest that trans-cis isomerization of 1 and 2 after S1 excitation is governed by the same mechanism. Since 1 cannot isomerize by a simple large-amplitude rotation of one of the phenyl rings about the central NN bond, the isomerization dynamics of both ABs should be better described as "inversion" at the N atom(s) rather than large-amplitude "rotation".

Synthesis of a Möbius aromatic hydrocarbon.

The defining feature of aromatic hydrocarbon compounds is a cyclic molecular structure stabilized by the delocalization of pi electrons that, according to the Hückel rule, need to total 4n + 2 (n = 1,2, em leader ); cyclic compounds with 4n pi electrons are antiaromatic and unstable. But in 1964, Heilbronner predicted on purely theoretical grounds that cyclic molecules with the topology of a Möbius band--a ring constructed by joining the ends of a rectangular strip after having given one end half a twist--should be aromatic if they contain 4n, rather than 4n + 2, pi electrons. The prediction stimulated attempts to synthesize Möbius aromatic hydrocarbons, but twisted cyclic molecules are destabilized by large ring strains, with the twist also suppressing overlap of the p orbitals involved in electron delocalization and stabilization. In larger cyclic molecules, ring strain is less pronounced but the structures are very flexible and flip back to the less-strained Hückel topology. Although transition-state species, an unstable intermediate and a non-conjugated cyclic molecule, all with a Möbius topology, have been documented, a stable aromatic Möbius system has not yet been realized. Here we report that combining a 'normal' aromatic structure (with p orbitals orthogonal to the ring plane) and a 'belt-like' aromatic structure (with p orbitals within the ring plane) yields a Möbius compound stabilized by its extended pi system.

Ethynylogization of a coarctate fragmentation

Coarctate reactions form a separate class of elementary closed-shell processes in addition to polar and pericyclic reactions. Hence, they also follow a different homology principle. Whereas vinylogous polar and pericyclic reactions differ in the length of the reacting system by a double bond, coarctate reactions can be homologized (ethynylogized) by extending a known system by a triple bond. The prediction, which is based on theoretical considerations, is confirmed experimentally by the fragmentation of cyclopropylethynyl nitrene to cyano acetylene and ethylene, a reaction that is "ethynyloguous" to the known fragmentation of cyclopropyl nitrene to ethylene and HCN.

Reaction planning: computer-aided discovery of a novel elimination reaction.

Algorithms based on graph theory and implemented in a computer program have been used to search for unprecedented reactions. This approach is illustrated by a systematic and exhaustive screening of pericyclic reactions in order to find new reactions useful in the synthesis of conjugated dienes. Two reactions were found. They were optimized by structural variation with the aid of quantum-chemical calculations and were then experimentally verified.