Iodination of organic substrates with halide salts and H2O2 using an organotelluride catalyst.

[figure: see text] Organotelluride 1 is a water-soluble catalyst for the oxidation of iodide with hydrogen peroxide in pH 6 phosphate buffer. In two-phase systems, organic substrates are efficiently iodinated using 0.8 mol % of catalyst. Water-soluble substrates are iodinated without an organic cosolvent.

Double-level "orthogonal" dynamic combinatorial libraries on transition metal template.

Dynamic combinatorial libraries are mixtures of compounds that exist in a dynamic equilibrium and can be driven to compositional self adaptation via selective binding of a specific assembly of certain components to a molecular target. We present here an extension of this initial concept to dynamic libraries that consists of two levels, the first formed by the coordination of terpyridine-based ligands to the transition metal template, and the second, by the imine formation with the aldehyde substituents on the terpyridine moieties. Dialdehyde 7 has been synthesized, converted into a variety of ligands, oxime ethers L(11)-L(33) and acyl hydrazones L(44)-L(77), and subsequently into corresponding cobalt complexes. A typical complex, Co(L(22))(2)(2+) is shown to engage in rapid exchange with a competing ligand L(11) and with another complex, Co(L(22))(2)(2+) in 30% acetonitrile/water at pH 7.0 and 25 degrees C. The exchange in the corresponding Co(III) complexes is shown to be much slower. Imine exchange in the acyl hydrazone complexes (L(44)-L(77)) is strongly controlled by pH and temperature. The two types of exchange, ligand and imine, can thus be used as independent equilibrium processes controlled by different types of external intervention, i.e., via oxidation/reduction of the metal template and/or change in the pH/temperature of the medium. The resulting double-level dynamic libraries are therefore named orthogonal, in similarity with the orthogonal protecting groups in organic synthesis. Sample libraries of this type have been synthesized and showed the complete expected set of components in electrospray ionization MS.

A selenopyrylium photosensitizer for photodynamic therapy related in structure to the antitumor agent AA1 with potent in vivo activity and no long-term skin photosensitization.

Cationic chalcogenopyrylium dyes 5 were synthesized in six steps from p-aminophenylacetylene (9), have absorption maxima in methanol of 623, 654, and 680 nm for thio-, seleno-, and telluropyrylium dyes, respectively, and generate singlet oxygen with quantum yields [Phi((1)O(2))] of 0.013, 0.029, and 0.030, respectively. Selenopyrylium dye 5-Se was phototoxic to cultured murine Colo-26 and Molt-4 cells. Initial acute toxicity studies in vivo demonstrate that, at 29 mg (62 micromol)/kg, no toxicity was observed with 5-Se in animals followed for 90 days under normal vivarium conditions. In animals given 10 mg/kg of 5-Se via intravenous injection, 2-8 nmol of 5-Se/g of tumor was found at 3, 6, and 24 h postinjection. Animals bearing R3230AC rat mammary adenocarcinomas were treated with 10 mg/kg of 5-Se via tail-vein injection and with 720 J cm(-2) of 570-750-nm light from a filtered tungsten lamp at 200 mW cm(-2) (24 h postinjection of 5-Se). Treated animals gave a tumor-doubling time of 9 +/- 4 days, which is a 300% increase in tumor-doubling time relative to the 3 +/- 2 days for untreated dark controls. Mechanistically, the mitochondria appear to be a target. In cultured R3230AC rat mammary adenocarcinoma cells treated with 0.1 and 1.0 microM 5-Se and light, mitochondrial cytochrome c oxidase activity was inhibited relative to cytochrome c oxidase activity in untreated cells. Irradiation of isolated mitochondrial suspensions treated with 10 microM dye 5-Se inhibited cytochrome c oxidase activity. The degree of enzyme inhibition was abated in a reduced oxygen environment. Superoxide dismutase, at a final concentration of 30 U, did not alter the photosensitized inhibition of mitochondrial cytochrome c oxidase by dye 5-Se. The data suggest that singlet oxygen may play a major role in the photosensitized inhibition of mitochondrial cytochrome c oxidase.

Water-soluble, core-modified porphyrins as novel, longer-wavelength-absorbing sensitizers for photodynamic therapy.

Water-soluble, core-modified 5,10,15, 20-tetrakis(4-sulfonatophenyl)-21,23-dithiaporphyrin (1) and 5,10,15, 20-tetrakis(4-sulfonatophenyl)-21,23-diselenaporphyrin (2) were prepared as the tetrasodium salts by the sulfonation of 5,10,15, 20-tetraphenyl-21,23-dithiaporphyrin (3) and -21, 23-diselenaporphyrin (4), respectively, with sulfuric acid. Compounds 3 and 4 were prepared by the condensation of pyrrole with either 2,5-bis(phenylhydroxymethyl)thiophene (5) or 2, 5-bis(phenylhydroxymethyl)selenophene (6) in propionic acid. The addition of benzaldehyde to 2,5-dilithiothiophene or 2, 5-dilithioselenophene gives 5 or 6, respectively, as a nearly equimolar mixture of meso- and d,l-diastereomers. Careful crystallization of 5 gives a single diastereomer by removing the crystalline product from the equilibrating mixture of diastereomers in solution. Photodynamic therapy (PDT) with 1 has an LD(50) of less than 25 microg/mL against Colo-26 cells in culture and exhibits a lethal dose for 90% or more at concentrations greater than 50 microg/mL. In contrast, PDT with 5,10,15, 20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS(4)) requires concentrations of greater than 100 microg/mL to achieve LD(50). Neither 1 nor TPPS(4) shows significant photoactivity against the murine T-cell line, MOLT-4, above the dark toxicity. Sensitizer 1 shows no toxicity or side effects in BALB/c mice observed for 30 days following a single intravenous injection of 10 mg (9.1 micromol)/kg. Distribution studies show that sensitizer 1 accumulates in the tumors of BALB/c mice bearing Colo-26 or EMT-6 tumors with sensitizer concentration roughly doubling as the dosage of 1 increased from 5 to 10 mg/kg. In vivo studies show that PDT with sensitizer 1 at both 3.25 and 10 mg/kg with 135 J cm(-2) of 694-nm light is effective against Colo-26 tumors in BALB/c mice.

2,4,6-triarylchalcogenopyrylium dyes related in structure to the antitumor agent AA1 as in vitro sensitizers for the photodynamic therapy of cancer.

Cationic chalcogenopyrylium dyes 2-4 were synthesized in six steps from 4-(dimethylamino)phenylethyne (7), have absorption maxima in methanol of 594, 631, and 672 nm, respectively, and generate singlet oxygen with quantum yields [Phi((1)O(2))] of 0.020, 0.064, and 0.037, respectively. Dyes 2-4 are hydrolytically more stable than other chalcogenopyrylium dyes evaluated previously as sensitizers for photodynamic therapy. At 10 microM final concentration, all dyes 2-4 inhibited cytochrome c oxidase during irradiation of tumor mitochondrial suspensions treated with 10 microM dye. The degree of enzyme inhibition was abated in a reduced oxygen environment and in the presence of imidazole, a singlet oxygen trap. Superoxide dismutase, at a final concentration of 30 U, did not alter the photosensitized inhibition of mitochondrial cytochrome c oxidase by dyes 2-4. These data suggest that singlet oxygen may play a major role in the photosensitized inhibition of mitochondrial cytochrome c oxidase. Irradiation of R3230AC rat mammary adenocarcinoma cells in the presence of dyes 2-4 caused a significant loss in cell viability with thiopyrylium dye 2 displaying the greatest phototoxicity. Initial acute toxicity studies in vivo demonstrate that, at 10 mg/kg, none of the three dyes displayed overt toxicity.

Synthesis and evaluation of chalcogenopyrylium dyes as potential sensitizers for the photodynamic therapy of cancer.

A series of thiopyrylium (2), selenopyrylium (3), and telluropyrylium dyes (4) was prepared via the addition of Grignard reagents to either 2, 6-di(4-dimethylamino)phenylchalcogenopyran-4-ones (5a) or 2-[4-(dimethylamino)phenyl]-6-phenylchalcogenopyran-4-ones (5b) followed by elimination and ion exchange to give the chloride salts. The absorption spectra and quantum yields for singlet oxygen generation of these dyes suggested that the dyes would have utility as sensitizers for PDT. Selenopyrylium dyes 3a and 3d with quantum yields for singlet oxygen generation of 0.040 and 0.045, respectively, were phototoxic to Colo-26 cells in culture. The toxicity of the dyes 2-4 was evaluated in clonogenic assays of human carcinoma cell lines. Importantly, the presence of a sulfur, selenium, or tellurium heteroatom in the molecules had no predictable impact on the toxicity of any particular dye set. Substituents at the 2-, 4-, and 6-positions of the dye had a much greater impact on cytotoxicity. The IC(50) values determined in the clonogenic assays did not correlate with chemical properties in the dye molecules such as reduction potential or lipophilicity. Initial in vivo toxicity studies showed no toxicity for these dyes at dosages between 7.2 and 38 micromol/kg in BALB/c mice.

Kinetic fluorimetric determination of Cu(II) and Zn(II) by their incorporation reactions into a water-soluble porphyrin.

Kinetics of incorporation of Cu, Zn, Fe, Co, Ni and Mn divalent ions into coproporphyrin-I in imidazole buffer solution, pH 7.0, has been studied by monitoring the decrease in fluorescence intensity of the free base porphyrin. All reactions followed simple second-order rate law, the rate constants being decreased in the order Zn > Cu >> Co > Fe >> Mn, Ni. the kinetic fluorimetric method for the determination of Cu(II) and Zn(II) using their incorporation reactions into the porphyrin was developed. Initial rate and fixed-time methods were used to construct calibration graphs over the range 0-1.0 x 10(-5)M of both metals. The analytical characteristics of the method and effect of foreign ions were determined. In the presence of sodium thiosulphate as the masking reagent the determination of micromolar concentrations of Zn in the presence of a 10-fold excess of Cu is possible.

Kinetics of oxidation of o-dianisidine by hydrogen peroxide in the presence of antibody complexes of iron(III) coproporphyrin.

The complex of iron(III) coproporphyrinI (FeCPI) with antibody D5E3 was studied as an artificial peroxidase, using o-dianisidine as a substrate. At saturation with respect to antibody, the initial rates of o-dianisidine oxidation are practically the same for free and bound FeCPI at a concentration 5 x 10(-9)M, but the catalytic rate constant (kc) for bound FeCPI exceed (kc) for free FeCPI by two- to three-fold. This difference can be explained by a real enhancement of (kc) at the antibody-active site. The dependence of initial rates of the reaction on substrate concentrations obeyed Michaelis-Menten kinetics and revealed substrate activation at high concentrations of o-dianisidine. A comparison of the Stern-Volmer constants for o-dianisidine-induced quenching of the porphyrin fluorescence proves that antibody-bound coproporphyrin is equivalently accessible to the substrate as protoporphyrin bound to apoperoxidase from horseradish peroxidase (HRP). Based on analysis of the (kc) dependence on H2O2 concentrations in the FeCPI-antibody system, we suggest that interaction with hydrogen peroxide is the rate-limiting step for the oxidation reaction.