Cationic arene ruthenium(II) complexes with chelating P-functionalized alkyl phenyl sulfide and sulfoxide ligands as potent anticancer agents.

The synthesis and characterization of cationic ruthenium(II) complexes of the type [Ru(η(6)-p-cym)Cl{Ph(2)P(CH(2))(n)S(O)(x)Ph-κP,κS}][PF(6)] (n = 1-3; x = 0, 1; p-cym = p-cymene) are presented. Furthermore, their high biological potential even against cisplatin-resistant tumor cell lines and their structure-activity relationships are discussed.

The synthesis, spectroscopic, X-ray characterization and in vitro cytotoxic testing results of activity of five new trans-platinum(IV) complexes with functionalized pyridines.

Platinum(IV) complexes with general formulas [Pt(L(1-2))(2)Cl(4)], where L(1-2) are 3-acetylpyridine (1) and 4-acetylpyridine (2) respectively, and [Pt(HL(3-5))(2)Cl(2)], where H(2)L(3-5) are 2,3-pyridinedicarboxylic acid (3), 2,4-pyridinedicarboxylic acid (4) and 2,5-pyridinedicarboxylic acid (5) respectively, were prepared by the reaction of K(2)[PtCl(6)] with the corresponding ligand in 1:2 M ratio in water. The complexes were characterized by elemental analysis and IR and NMR spectroscopy. The structures of complexes 2 and 5 were determined by X-ray crystallography, which revealed the trans orientation of chloride anions around platinum(IV) in the case of both complexes. The antiproliferative activity was investigated in six tumor cell lines (human cervical carcinoma cells (HeLa), murine melanoma cells (B16), human breast carcinoma cells (MDA-MB-453), human colon carcinoma cells (LS-174), transformed human umbilical vein endothelial cells (EA.hy 926) and murine endothelial cells (MS1)) and in one non-tumor cell line-human fetal lung fibroblast cells (MRC-5). Cytotoxicity studies indicated that Pt(IV) complexes with acetyl-substituted pyridine ligands exhibit significantly higher in vitro antiproliferative activity than the complexes with carboxylato-substituted pyridines. Complexes 1 and 2 showed antiproliferative activity in all tested tumor cell lines, with the highest potential in human endothelial cells EA.hy 926, since they had IC(50) values of 13.8 ± 5.8 µM and 23.4 ± 3.3 µM, respectively and were more active than cisplatin. Complexes 1 and 2 exhibited lower toxicity against the non-tumor human lung fibroblast cell line (MRC-5) than against most of the tested tumor cell lines.

Highly active neutral ruthenium(II) arene complexes: synthesis, characterization, and investigation of their anticancer properties.

Reactions of ω-diphenylphosphino-functionalized alkyl phenyl sulfides Ph(2)P(CH(2))(n)SPh (n=1, L1; 2, L2; 3, L3), sulfoxides Ph(2)P(CH(2))(n)S(O)Ph (n=1, L4; 2, L5; 3, L6) and sulfones Ph(2)P(CH(2))(n)S(O)(2)Ph (n=1, L7; 2, L8; 3, L9) with the dinuclear chlorido bridged ruthenium(II) complex [{Ru(η(6)-p-cymene)Cl(2)}(2)] afforded mononuclear ruthenium(II) complexes of the type [Ru(η(6)-p-cymene)Cl(2){Ph(2)P(CH(2))(n)S(O)(x)Ph-κP}] (n/x=1/0, 1; 2/0, 2; 3/0, 3; 1/1, 4; 2/1, 5; 3/1, 6; 1/2, 7; 2/2, 8; 3/2, 9) having the P(∩)S(O)(x) ligands κP coordinated. The complexes were characterized by (1)H, (13)C and (31)P NMR spectroscopy. The crystal structures of complexes 2, 7·CH(2)Cl(2) and 8 were determined by X-ray diffraction analysis. All complexes have been screened for cytostatic activity against cell lines 518A2, 8505C, A253, MCF-7, and SW480. In vitro biological experiments demonstrate that these compounds are active toward the used cell lines. The ruthenium(II) complex [Ru(η(6)-p-cymene)Cl(2){Ph(2)P(CH(2))(2)SPh-κP}] (2) is the most active compound in the human cancer cell line MCF-7 with the IC(50) value 1.4 µM lower than cisplatin (2.0 µM).

On the isomerization of cyclooctyne into cycloocta-1,3-diene: synthesis, characterization and structure of a dinuclear platinum(II) complex with a µ-η2:η2-1,3-COD ligand.

The Zeise's salt type cyclooctyne compound [K(18C6)][PtCl(3)(COC)] (1; COC = cyclooctyne; 18C6 = 18-crown-6) was found to react in chloroform solution at room temperature within several weeks yielding the dinuclear cyclooctadiene compound [K(18C6)](2)[(PtCl(3))(2)(µ-η(2):η(2)-1,3-COD)] (2; 1,3-COD = cycloocta-1,3-diene) and non-coordinated cycloocta-1,3-diene. The identity of 2 was confirmed by microanalysis, NMR spectroscopy ((1)H, (13)C) and electrospray ionization mass spectrometry (ESI-MS). A single-crystal X-ray diffraction analysis of 2 exhibited a bridging µ-η(2):η(2)-cycloocta-1,3-diene ligand with non-conjugated double bonds each coordinated to a PtCl(3) fragment. On the basis of DFT calculations as well as energy decomposition analyses (EDA), charge decomposition analyses (CDA) and natural bond orbital (NBO) analyses the peculiarities of the nature of the Pt-C bonds in the dinuclear complex anion [(PtCl(3))(2)(µ-η(2):η(2)-1,3-COD)](2-) (2a') compared with those in mononuclear olefin complexes of Zeise's salt type [PtCl(3)L](-) (L = η(2)-1,3-COD, 3a'; cis-but-2-ene, 4a'; COE, 5a'; COE = cyclooctene) are discussed. Furthermore, the driving force for the strongly exergonic reaction with formation of the cyclooctadiene complex 2a' was found to be a significant release of ring strain of the cyclooctyne ligand in the starting compound 1.

In vitro anticancer studies of alpha- and beta-D-glucopyranose betulin anomers.

Four derivatives of betulin containing a D-glucopyranosyl moiety at C3 position were synthesized and characterized by (1)H and (13)C NMR spectroscopy as well as mass spectrometry. The crystal structure of 28-O-acetylbetulin-3-yl-beta-D-(2',3',4',6'-tetra-O-acetyl)glucopyranoside was determined. The compounds were tested against fifteen tumor cell lines of different histogenic origins. The alpha- and beta-anomers of 28-O-acetylbetulin-3-yl-D-glucopyranoside, exerted a dose dependent antiproliferative action towards the tumor cell lines. Treatment of HCT-116 cells for 24h induced apoptosis, which was confirmed by the appearance of a typical ladder pattern in the DNA fragmentation assay and cell cycle analysis. The alpha- and beta-anomers of 28-O-acetylbetulin-3-yl-D-glucopyranoside seem to induce apoptosis by activation of different upstream caspases on colon cancer HCT-116 cell line.