Georg Süss-Fink

Ruthenium Porphyrin Compounds for Photodynamic Therapy of Cancer

Five 5,10,15,20-tetra(4-pyridyl)porphyrin (TPP) areneruthenium(II) derivatives and a p-cymeneosmium and two pentamethylcyclopentadienyliridium and -rhodium analogues were prepared and characterized as potential photosensitizing chemotherapeutic agents. The biological effects of all these derivatives were assessed on human melanoma tumor cells, and their cellular uptake and intracellular localization were determined. All molecules, except the rhodium complex which was not cytotoxic, demonstrated comparable cytotoxicity in the absence of laser irradiation. The ruthenium complexes exhibited excellent phototoxicities toward melanoma cells when exposed to laser light at 652 nm. Cellular uptake and localization microscopy studies of [Ru 4(eta (6)-C 6H 5CH 3) 4(TPP)Cl 8] and [Rh 4(eta (5)-C 5Me 5) 4(TPP)Cl 8] revealed that they accumulated in the melanoma cell cytoplasm in granular structures different from lysosomes. The fluorescent porphyrin moiety and the metal component were localized in similar structures within the cells. Thus, the porphyrin areneruthenium(II) derivatives represent a promising new class of organometallic photosensitizers able to combine chemotherapeutic activity with photodynamic therapeutic treatment of cancer.

Organometallic cages as vehicles for intracellular release of photosensitizers.

Water-soluble metalla-cages were used to deliver hydrophobic porphin molecules to cancer cells. After internalization, the photosensitizer was photoactivated, significantly increasing the cytotoxicity in cells. During the transport, the photosensitizer remains nonreactive to light, offering a new strategy to tackle overall photosensitization, a limitation often encountered in photodynamic therapy.

Oxidations by the system "hydrogen peroxide-manganese(IV) complex-carboxylic acid" Part 3. Oxygenation of ethane, higher alkanes, alcohols, olefins and sulfides

The manganese(IV) complex salt [L2Mn2O3](PF6)2 (L = 1,4,7-trimethyl-1,4,7-triazacyclononane) (compound 1, see Scheme 1) very efficiently catalyzes the hydroperoxidation of saturated hydrocarbons, including ethane by H2O2 in acetontitrile or nitromethane solution at low (room or lower) temperature, provided a carboxylic (typically acetic) acid is present. The hydroperoxidation of tertiary positions in disubstituted cyclohexanes proceeds with partial retention of configuration in nitromethane or acetonitrile solution, while the stereoselectivity of the reaction is only negligible in acetone solution. The system “H2O2–compound 1–MeCO2H” also transforms secondary alcohols into the corresponding ketones with quantitative yields at room temperature within a few minutes; the yields of aldehydes and carboxylic acids in the oxidation of primary alcohols are lower. Terminal aliphatic olefins such as hexene-1 are quantitatively epoxidized by the same system in acetonitrile at room temperature within 20 min, while the epoxide yield in the analogous reaction with styrene attains only 60% under the same conditions. Finally, dimethylsulfide can be quantitatively and selectively converted into dimethylsulfoxide within 3 h at room temperature. The system “tert-BuOOH–compound 1” also oxidizes alkanes, addition of acetic acids has less pronounced effect on the direction and efficiency of the reaction. Two other checked derivative of Mn(IV) (compounds 2 and 3) as well a porphyrin complex of Mn(III) (compound 4) exhibited lower activity in catalysis of alkane oxidation with tert-BuOOH.

Oxidations by the system “hydrogen peroxide - manganese(IV) complex - acetic acid” — Part II. Hydroperoxidation and hydroxylation of alkanes in acetonitrile

Abstract Higher alkanes (cyclohexane, n -pentane, n -heptane, methylbutane, 2- and 3-methylpentanes, 3-methylhexane, cis - and trans -decalins) are oxidized at 20 °C by H 2 O 2 in air in acetonitrile (or nitromethane) solution in the presence of the manganese(IV) salt [L 2 Mn 2 O 3 ](PF 6 ) 2 (L = 1,4,7-trimethyl-1,4-7-triazacyclononane) as the catalyst. An obligatory component of the reaction mixture is acetic acid. Turnover numbers attain 3300 after 2 h, the yield of oxygenated products is 46% based on the alkane. The oxidation affords initially the corresponding alkyl hydroperoxide as the predominant product, however later these compounds decompose to produce the corresponding ketones and alcohols. Regio- and bond selectivities of the reaction are high: C(1) : C(2) : C(3) : C(4) ≈ 1 : 40 : 35 : 35 and 1° : 2° : 3° is 1 : (15–40) : (180–300). The reaction with both isomers of decalin gives (after treatment with PPh 3 ) alcohols hydroxylated in the tertiary positions with the cis/trans ratio of ∼ 2 in the case of cis -decalin, and of ∼ 30 in the case of trans -decalin (i.e. in the latter case the reaction is stereospecific). Light alkanes (methane, ethane, propane, normal butane and isobutane) can be also easily oxidized by the same reagent in acetonitrile solution, the conditions being very mild: low pressure (1–7 bar of the alkane) and low temperature (−22 to +27 °C). Catalyst turnover numbers attain 3100, the yield of oxygenated products is 22% based on the alkane. The yields of oxygenates are higher at low temperatures. The ratio of products formed (hydroperoxide: ketone: alcohol) depends very strongly on the conditions of the reaction and especially on the catalyst concentration (at higher catalyst concentration the ketone is predominantly produced).

Water-soluble arene ruthenium catalysts containing sulfonated diamine ligands for asymmetric transfer hydrogenation of α-aryl ketones and imines in aqueous solution

A new family of nine cationic organometallic aqua complexes of the type [(arene)Ru(RSO2N∩NH2)(OH2)]+ (1–9), containing chiral N,N-chelating ligands, has been synthesised and isolated as the tetrafluoroborate salts, which are water-soluble and stable to hydrolysis. The enantiopure complexes 1–9 catalyse the transfer hydrogenation of prochiral aryl ketones and imines in aqueous solution to give the corresponding alcohols and amines with good conversion and enantioselectivity. This method gives an environmentally friendly access, for instance, to isoquinoline alkaloids by asymmetric catalysis in water.

Self-assembled hexanuclear arene ruthenium metallo-prisms with unexpected double helical chirality

Self-assembly of 2,4,6-tripyridyl-1,3,5-triazine (tpt) subunits with arene ruthenium building blocks and oxalato bridges affords cationic triangular metallo-prisms of the type [Ru6(arene)6(tpt)2(C2O4)3]6+ (arene = C6Me6 and p-Pr(i)C6H4Me); the unexpected double helical chirality of the metallo-prisms observed in the solid state persists in solution giving rise to two different stereodynamic processes as demonstrated by NMR enantiodifferentiation experiments.

Hydroperoxidation of methane and other alkanes with H2O2 catalyzed by a dinuclear iron complex and an amino acid

Abstract The compound [Fe2(HPTB)(μ-OH)(NO3)2](NO3)2·CH3OH·2H2O ( 1 ) containing a dinuclear iron(III) complex in which HPTB=N,N,N′,N′-tetrakis(2-benzimidazolylmethyl)-2-hydroxo-1,3-diaminopropane catalyzes the oxidation of alkanes with hydrogen peroxide in acetonitrile solution at room temperature only if certain amino acids (pyrazine-2-carboxylic, pyrazine-2,3-dicarboxylic or picolinic acid) are added to the reaction mixture. Alkyl hydroperoxides are formed as main reaction products. The turnover numbers attain 140 for cyclohexane, 21 for ethane and four for methane oxidation. The oxidation proceeds non-stereoselectively and bond selectivity parameters are low which testifies the participation of hydroxyl radicals in alkane functionalization.

Alkane oxidation with hydrogen peroxide catalyzed homogeneously by vanadium-containing polyphosphomolybdates

Alkanes (cyclooctane, n-octane, adamantane, ethane) can be efficiently oxidized by hydrogen peroxide in acetonitrile using tetra-n-butylammonium salts of the vanadium-containing polyphosphomolybdates [PMo11VO40] 4− and [PMo6V5O39] 12− as catalysts. The oxidation of alkanes gives rise to the corresponding alkyl hydroperoxides as the main products, which slowly decompose in the course of the reaction to produce the corresponding ketones (aldehydes) and alcohols. The reaction in acetic acid and water is much less efficient. The oxidation of cyclooctane at 60 ◦ C in acetonitrile gives within 9 h oxygenates with turnover numbers >1000 and yields >30% based on the alkane. Pyrazine-2-carboxylic acid added as co-catalyst accelerates the reaction but does not enhance the product yield. The oxidation of the cis- and trans-isomers of decalin proceeds without retention of configuration. The mechanism assumed involves the reduction of V(V) to V(IV) by a first molecule of hydrogen peroxide, followed by the reaction of V(IV) with a second H2O2 molecule to generate hydroxyl radicals. The latter abstract a hydrogen atom from the alkane, RH, leading to alkyl radicals, R • , which rapidly react with aerobic oxygen. The alkyl peroxy

Supramolecular cluster catalysis: benzene hydrogenation catalyzed by a cationic triruthenium cluster under biphasic conditions.

At the interface of homogeneous, heterogeneous, and enzymatic catalysis is the catalytic hydrogenation of benzene to give cyclohexane by the triruthenium cluster 1. Experimental evidence and molecular modeling studies strongly support a catalytic mechanism in which the aromatic substrate is hydrogenated in the hydrophobic pocket spanned by the three η6-bound arene ligands without being coordinated to a Ru center.

Thiophenolato-bridged dinuclear arene ruthenium complexes: a new family of highly cytotoxic anticancer agents

New cationic diruthenium complexes of the type [(arene)(2)Ru(2)(SPh)(3)](+), arene being C(6)H(6), p-(i)PrC(6)H(4)Me, C(6)Me(6), C(6)H(5)R, where R = (CH(2))(n)OC(O)C(6)H(4)-p-O(CH(2))(6)CH(3) or (CH(2))(n)OC(O)CH=CHC(6)H(4)-p-OCH(3) and n = 2 or 4, are obtained from the reaction of the corresponding precursor [(arene)RuCl(2)](2) and thiophenol and isolated as their chloride salts. The complexes have been fully characterised by spectroscopic methods and the solid state structure of [(C(6)H(6))(2)Ru(2)(SPh)(3)](+), crystallised as the hexafluorophosphate salt, has been established by single crystal X-ray diffraction. The complexes are highly cytotoxic against human ovarian cancer cells (cell lines A2780 and A2780cisR), with the IC(50) values being in the submicromolar range. In comparison the analogous trishydroxythiophenolato compounds [(arene)(2)Ru(2)(S-p-C(6)H(4)OH)(3)]Cl (IC(50) values around 100 μM) are much less cytotoxic. Thus, it would appear that the increased antiproliferative effect of the arene ruthenium complexes is due to the presence of the phenyl or toluyl substituents at the three thiolato bridges.