Antitumour Organometallics. III. In Vivo Activity of Diphenylantimony(III) and Diorganotin(IV) Dithiophosphorus Derivatives Against P388 Leukemia

Diphenylantimony(III) and diorganotin(IV) derivatives of dithiophosphorus ligands, i.e. Ph2SbS2PR′2 (R′ = Ph, OPr-i) and R2Sn(S2PR′2)2 (R = n-Bu, Ph, R′ = Ph; R = Ph, R′ = OPr-i), have been screened against P388 leukemia in mice. All the compounds showed marginal activity towards this tumor system, some of them increasing the life span of the animals with more than 20%. The best results were obtained with (di-iso-propylphosphorodithioato)diphenylantimony(III) which exhibited a T/C value of 136%, at a dose of 5 mg/kg, administered on days 1,2 and 3 after tumor transplantation

Solvolysis of the Tumor-Inhibiting Ru(III)-Complex trans-Tetrachlorobis(Indazole)Ruthenate(III)

The ruthenium(III) complex Hlnd trans-[RuCl4,(ind)2], with two trans-standing indazole (ind) ligands bound to ruthenium via nitrogen, shows remarkable activity in different tumor models in vitro and in vivo. The solvolysis of the complex trans-[RuCl4,(ind)2]- has been investigated by means of spectroscopic techniques (UV/vis, NMR)in different solvents. We investigated the indazolium as well as the sodium salt, the latter showing improved solubility in water. In aqueous acetonitrile and ethanol the solvolysis results in one main solvento complex. The hydrolysis of the complex is more complicated and depends on the pH of the solution as well as on the buffer system

The binding properties of two antitumor ruthenium(III) complexes to apotransferrin.

The interaction of two ruthenium(III) complexes exhibiting high anticancer activity, namely trans-indazolium(bisindazole)tetrachlororuthenate(III) (ru-ind) and trans-imidazolium(bisimidazole)tetrachlororuthenate(III) (ru-im), with human serum apotransferrin has been investigated through spectroscopic and chromatographic techniques with the ultimate goal of preparing adducts with good selectivity for cancer cells. Whereas the binding of ru-im to human serum apotransferrin takes several hours, ru-ind, the less toxic complex, gives rise to a well defined 2:1 complex within a few minutes. We have ascertained that ru-ind binding occurs around the iron binding sites; binding does not occur in the absence of bicarbonate, and this anion dictates the kinetic and mechanistic characteristics of protein binding of ru-ind. The two ruthenium(III) complexes do not behave as iron(III) complexes, e.g. Fe(EDTA) or Fe(nitrilotriacetate), which lose their respective ligands when binding apotransferrin, but the N-heterocycles remain attached to the metal in the protein-bound species. Reversion of binding is obtained by acidification in the presence of chelators such as citrate or ATP. In comparison with cisplatin and its deactivation by serum proteins, our results indicate that other metal complexes such as ru-ind could use transferrin as a drug delivery system. Furthermore, the rapid protein binding of ru-ind seems to be related to a lower toxicity while still exhibiting high antitumor activity

Synthesis, Characterization and Solution Chemistry of trans-Indazoliumtetrachlorobis(Indazole)Ruthenate(III), a New Anticancer Ruthenium Complex. IR, UV, NMR, HPLC Investigations and Antitumor Activity. Crystal Structures of trans-1-Methyl-Indazoliumtetrachlorobis-(1-Methylindazole)Ruthenate(III) and its Hydrolysis Product trans-Monoaquatrichlorobis-(1-Methylindazole)-Ruthenate(III)

Besides intensive studies into the synthesis of the complex trans-Hlnd[RuCl4(ind)2] (Ind = indazole) 1, which differs remarkably from the usual method for the complexes of the HL[RuCl4L2] - type, competitive products and hydrolysis of this species are described. Stability and pseudo-first-order rate constant under physiological conditions of complex 1 in comparison with the analogous imidazole complex trans-Hlm[RuCl4im2] (Im = imidaZole) ICR were examined by means of HPLC, UV and conductivity measurements (Kobs.(1) = 1.55 × 10-4 s-1; Kobs.(ICR) = 9.10 × 10-4 s-1). An attempt was made to elucidate the bonding conditions in 1 by studying the reactions of Ru(lll) and the two N-methyl isomers of indazole. It can be expected that bonding in the unsubstituted ligand should occur via the N2 nitrogen. The molecular structures of the complex trans-H(1-Melnd)[RuCl4(1-Melnd)2] × 1H2O (1-Melnd = 1-methylindazole) 6 and its hydrolysis product in aqueous solution [RuCl4(H2O)(1-Melnd)2] 7 were determined crystallographically. After anisotropic refinement of F values by least squares, R is 0.053 for 6 and 0.059 for 7. Both complexes crystallize with four molecules in a unit cell of monoclinic symmetry. The space group is P2.1/n for 6 with cell dimensions a = 10.511Å, b = 13.87Å, c = 19.93Å, and β = 98.17° and C2/c for 7 with a = 19.90Å, b = 10.94Å, c = 8.490Å and β = 96.74 ° The fact that the aqua species 7 could be isolated after dissolving 6 in a water/acetone solution confirmed the theory of many Ru(lll) complexes being initially transformed, under physiological conditions, into aqua complexes in a first and often rate-determining hydrolysis step. Compounds 1 and ICR are potent antitumor agents which exhibit activity against a variety of tumor cells and experimental tumor models in animals, including autochthonous colorectal tumors. Clinical studies with 1 are in preparation

Synthesis, Characterization and Molecular Structures of some Bismuth(III) Complexes with Thiosemicarbazones and Dithiocarbazonic Acid Methylester Derivatives with Activity against Helicobacter Pylori

The reactions of bismuth(III) nitrate pentahydrate and bismuth(III) chloride with heterocyclic thiosemicarbazones and derivatives of dithiocarbazonic acid methylester were used to synthesize the respective bismuth(III) complexes, which could be divided into five groups D-H because of their stoichiometrical properties and their molecular structures. The molecular structure and the near coordination sphere of the bismuth(III) central atom of four representative compounds were determined by single-crystal X-ray studies. Bis[1-azepanyl-4-(2-pyridyl)-2,3-diazapenta-1,3-diene-1-thiolato-N′,N3,S]bismuth(III) nitrate (5) belongs to group D. The two tridentate ligands and the nitrate ion surround the bismuth atom. The best description of the coordination sphere appears to be that of a distorted trigonal dodecahedron with one position occupied by the lone pair of the bismuth atom. Bis[1-azepanyl-4-(2-thienyl)-2,3-diazapenta-1,3-diene-1-thiolato-N3,S]bismuth(III) nitrate (9) is assigned to complex type E. Here, two deprotonated ligand molecules are coordinated to the bismuth(III) central atom as bidentate ligands. The structure of this complex can best be described as a distorted trigonal antiprism with a five-coordinated central atom. The two triangular faces are formed by the atoms S(4), N(6), O(11) and S(3), N(4) and the lone pair of the central atom. The two chelate rings are almost perpendicular to each other. Complex molecules of group F form dimeric units with bichloro-bridged bismuth atoms. The structure of di-μ-chlorobis[1-azepanyl-4-(2-pyridyl)-2,3-diazapenta-1,3-diene-1-thiolato-N′,N3,S-chloro]dibismuth(III) (15) can be described as two six-coordinated bismuth atoms, which are bound together via two bridging chlorine atoms. The two bismuth atoms Bi(1) and Bi(1a) and the two bridging chlorine atoms Cl(2) and Cl(2a) form the Bi2Cl2 plane. The two tridentate ligand molecules coordinate via the same atoms as shown in complex 5. In addition, they form two parallel planes, which are perpendicular to the Bi2Cl2 plane. With regard to the center of the Bi(1)-Bi(2) axis they are central point symmetrical, i.e. one pyridine ring lies above and the other beneath the Bi2Cl2 plane. Bismuth(III) chloride and pyridine-2-carboxaldehydethiosemicarbazone 1 b or 2-acetylpyridine-thiosemicarbazone 1 c form complexes of group G. Three chlorine atoms and a bidentate ligand are coordinated to the bismuth(III) central atom. The bidentate ligand bound to the central atom through the N(3) atom and the sulfur atom of the thioketo group. The structure of 18 is completely different from the structures of the bismuth(III) complexes discussed so far and was therefore assigned to group H. The bismuth central atom is coordinated with two ligands, which are bound in different ways. One of them is deprotonated. This ligand is bound to the central atom via the sulfur atom S(3) of the thiolate group and the N(5) atom. An interaction between the sulfur atom of the thiophene ring and the bismuth atom is not possible.The other ligand molecule is not deprotonated. This ligand is bound to the bismuth(III) cation merely via the sulfur atom S(1) of the thioketo group. The best description of the coordination sphere of the bismuth atom is that of a distorted square bipyramidal polyhedron. The square face is formed by the atoms S(3), N(5), Cl(1), the lone pair and the bismuth atom within. The axial positions are occupied by the atoms S(1) and Cl(2). The bond angle between S(1), Bi(1) and Cl(2) differs by about eight degrees from the value determined for a regular square bipyramidal polyhedron of 180 degrees

Synthesis and in vitro Antitumor Potency of (Cyclohexane-1,2-Diamine)Platinum(II) Complexes with Aminotris(Methylenephosphonic Acid) as Bone-Seeking Ligand

In order to develop platinum complexes with selective activity in primary and secondary bone malignancies and with the aim to optimize antitumor activity, platinum(II) complexes with aminotris(methylenephosphonic acid) as bone-seeking (osteotropic) ligand have been synthesized, characterized and tested in the cisplatin-sensitive ovarian carcinoma cell line CH1. As non-leaving diamine ligands, which are decisive for the cellular processing of DNA adducts, cis-R,S-cyclohexane-1,2-diamine, trans-S,S-cyclohexane-1,2-diamine and trans-R,R-cyclohexane-1,2-diamine have been used, resulting in complexes 1, 2, and 3, respectively. The cytotoxicity of the complexes under investigation decreases in the order 3 > 2 > 1 which is in accord with structure-activity relationships with other (cyclohexane-1,2- diamine)platinum(II) and platinum(IV) complexes: Both trans complexes (2 and 3) display a higher in vitro potency than the corresponding cis isomer (I), with the trans-R,R isomer (3) being the most active in this series. In comparison to the analogous (cyclohexane-1,2-diamine)platinum(II) complexes with bis(phosphonomethyl)aminoacetic acid as osteotropic carrier ligand, the cytotoxicity of 1-3 was found to be 1.5 – 2 fold higher, which is explainable by a different coordination mode of the phosphonic acid ligands (acetato versus phosphonato)