Ioannis Bratsos

A categorization of metal anticancer compounds based on their mode of action

The development of new metal anticancer compounds is a challenge for inorganic chemists. We have to face the fact that four decades of research in this field have only produced a small number of clinically used compounds, most often developed through serendipity rather than through rational chemical design. Nevertheless, by virtue of the wealth of knowledge acquired in these years, medicinal inorganic chemistry is probably mature for making significant steps forward and there are great expectations for future developments. With the aim of contributing to the rationalization of this field, we suggest here a categorization of metal anticancer compounds into five classes based on their mode of action: (i) the metal has a functional role, i.e. it must bind to the biological target; (ii) the metal has a structural role, i.e. it is instrumental in determining the shape of the compound and binding to the biological target occurs through non-covalent interactions; (iii) the metal is a carrier for active ligands that are delivered in vivo; (iv) the metal compound is a catalyst; and (v) the metal compound is photoactive and behaves as a photo-sensitizer. Selected examples for each category are given. The few metal anticancer drugs that are in clinical use are all believed to be functional compounds. Our classification, that is clearly focused on the metal compound and is independent from the nature of its bio-target(s)-most often still unknown-has the purpose of providing an intellectual tool that might be helpful in the rational development of new drugs.

1-(2-Picolyl)-substituted 1,2,3-triazole as novel chelating ligand for the preparation of ruthenium complexes with potential anticancer activity

The 1,4-disubstituted 1,2,3-triazole ligand prepared by click chemistry 1-(2-picolyl)-4-phenyl-1H-1,2,3-triazole (ppt) was investigated as novel chelating ligand for Ru(II) complexes with potential antitumor activity. The preparation and structural characterization, mainly by NMR spectroscopy in solution and by X-ray crystallography in the solid state, of four new Ru(II) complexes is reported: two isomeric Ru-dmso compounds, trans,cis-[RuCl(2)(dmso-S)(2)(ppt)] (1) and cis,cis-[RuCl(2)(dmso-S)(2)(ppt)] (2), and two half-sandwich Ru-[9]aneS(3) coordination compounds, [Ru([9]aneS(3))(dmso-S)(ppt)][CF(3)SO(3)](2) (3) and [Ru([9]aneS(3))Cl(ppt)][CF(3)SO(3)] (4). In all compounds ppt firmly binds to ruthenium in a bidentate fashion through the pyridyl nitrogen atom and the triazole N2, thus forming a puckered six-membered ring. The chemical behavior in aqueous solution of the water-soluble complexes 3 and 4 was studied by UV-Vis and NMR spectroscopy and compared to that of the previously described organometallic analogue [Ru(η(6)-p-cymene)Cl(ppt)][Cl] (5) in view of their potential antitumor activity. Compounds 3-5 were tested also in vitro for cytotoxic activity against two human cancer cell lines, one sensitive and one resistant to cisplatin, in comparison with cisplatin. Compound 4, the one that aquates faster, was found to be more cytotoxic than cisplatin against human lung squamose carcinoma cell line (A-549).

New Uses for Old Drugs: Attempts to Convert Quinolone Antibacterials into Potential Anticancer Agents Containing Ruthenium

Continuing the study of the physicochemical and biological properties of ruthenium-quinolone adducts, four novel complexes with the general formula [Ru([9]aneS3)(dmso-κS)(quinolonato-κ(2)O,O)](PF6), containing the quinolones levofloxacin (1), nalidixic acid (2), oxolinic acid (3), and cinoxacin (4), were prepared and characterized in solid state as well as in solution. Contrary to their organoruthenium analogues, these complexes are generally relatively stable in aqueous solution as substitution of the dimethylsulfoxide (dmso) ligand is slow and not quantitative, and a minor release of the quinolonato ligand is observed only in the case of 4. The complexes bind to serum proteins displaying relatively high binding constants. DNA binding was studied using UV-vis spectroscopy, cyclic voltammetry, and performing viscosity measurements of CT DNA solutions in the presence of complexes 1-4. These experiments show that the ruthenium complexes interact with DNA via intercalation. Possible electrostatic interactions occur in the case of compound 4, which also shows the most pronounced rate of hydrolysis. Compounds 2 and 4 also exhibit a weak inhibition of cathepsins B and S, which are involved in the progression of a number of diseases, including cancer. Furthermore, complex 2 displayed moderate cytotoxicity when tested on the HeLa cell line.

New half sandwich Ru(II) coordination compounds for anticancer activity.

With the aim of expanding the structure-activity relationship investigation, the series of Ru(II) half sandwich coordination compounds of the type [Ru([9]aneS3)(chel)(L)](n+) previously described by us (where [9]aneS3 is the neutral face-capping ligand 1,4,7-trithiacyclononane, chel is a neutral or anonic chelating ligand, L = Cl(-) or dmso-S, n = 0-2) was extended to 1,4,7-triazacyclononane ([9]aneN3). In addition, new neutral N-N, and anionic N-O and O-O chelating ligands, i.e. dach (trans-1,2-diaminocyclohexane), pic(-) (picolinate), and acac(-) (acetylacetonate), were investigated in combination with both [9]aneS3 and [9]aneN3. Overall, ten new half-sandwich complexes were prepared and fully characterized and their chemical behaviour in aqueous solution was established. The single-crystal X-ray structures of eight of them, including the versatile precursor [Ru([9]aneN3)(dmso-S)(2)Cl]Cl (9), were also determined. The results of in vitro antiproliferative tests performed on selected compounds against MDA-MB-231 human mammary carcinoma cells confirmed that, in this series, only compounds that hydrolyse the monodentate ligand at a reasonable rate show moderate activity, provided that the chelate ligand is a hydrogen bond donor.

New half sandwich-type Ru(II) coordination compounds characterized by the fac-Ru(dmso-S)3 fragment: influence of the face-capping group on the chemical behavior and in vitro anticancer activity

The Ru(II) complex fac-[RuCl(dmso-S)(3)(dmso-O)(2)][PF(6)] (P2) was found to be an excellent precursor for the facile preparation in high yield of half sandwich-type compounds of the general formula fac-[RuCl(dmso-S)(3)(N)(2)][PF(6)] (e.g. (N)(2) = 1,2-diaminoethane (en, 4), trans-1,2-diaminocyclohexane (dach, 5), or 2 NH(3) (6)). Neutral half sandwich-type compounds of the general formula fac-[RuCl(dmso-S)(3)(N-O)] where N-O is an anionic chelating ligand (e.g. N-O = picolinate (pic, 7)) are best prepared from the universal Ru(II)-dmso precursor cis-[RuCl(2)(dmso)(4)] (P1). These complexes, that were fully characterized in solution and in the solid state, are structurally similar to the anticancer organometallic compounds [Ru(η(6)-arene)(chel)Cl][PF(6)](n) but, in place of a face-capping arene, have the fac-Ru(dmso-S)(3) fragment. In contrast to what observed for the corresponding arene compounds, that rapidly hydrolyze the Cl ligand upon dissolution in water, compounds 4-6 are very stable and inert in aqueous solution. Probably their inertness is the reason why they showed no significant cytotoxicity against the MDA-MB-231 cancer cell line.

New Cationic and Neutral Ru(II)- and Os(II)-dmso carbonyl Compounds

The preparation and structural characterization of three cationic Ru(II)-dmso carbonyls and of four neutral mono- and dicarbonyl Os(II)-dmso derivatives is reported. The two monocarbonyl species fac-[Ru(CO)(dmso-O)3(dmso-S)2][PF6]2 (11) and cis,cis,cis-[RuCl(CO)(dmso-O)2(dmso-S)2][PF6] (12) were obtained from the neutral monocarbonyl precursor cis,trans,cis-[RuCl2(CO)(dmso-O)(dmso-S)2] (3) upon stepwise replacement of the chlorides with dmso, that binds in each case through the oxygen atom. The dicarbonyl cationic complex cis,cis,trans-[Ru(CO)2(dmso-O)2(dmso-S)Cl][PF6] (13) was instead obtained upon treatment of the neutral tricarbonyl precursor fac-[RuCl2(CO)3(dmso-O)] (8) with AgPF6 in the presence of DMSO: replacement of a Cl(-) with a dmso-O implied also the substitution of one CO ligand by another dmso (that binds through S trans to Cl). The Os(II) carbonyls trans,trans,trans-[OsCl2(CO)(dmso-O)(dmso-S)2] (17), trans,cis,cis-[OsCl2(CO)2(dmso-O)2] (18), cis,mer-[OsCl2(CO)(dmso-S)3] (19), and cis,trans,cis-[OsCl2(CO)(dmso-O)(dmso-S)2] (20) were obtained by treatment of the Os(II)-dmso precursors trans-[OsCl2(dmso-S)4] (14) and cis,fac-[OsCl2(dmso-O)(dmso-S)3] (15) with CO. Each one of them is structurally similar to an already known Ru(II) analog, even though--in agreement with the expected greater inertness of Os(II)--more forcing reaction conditions were required for their preparation. Interestingly, compound 20 could not be isolated in pure form, but only as a 1:1 cocrystallized mixture with its precursor 15. The dmso ligand is always bound through the oxygen atom when trans to CO. We are confident that the new Ru(II)- and Os(II)-dmso carbonyl species described here represent a contribution to expand the pool of complexes bearing some easily replaceable dmso ligands to be used as well-behaved precursors in inorganic synthesis.

Half-sandwich RuII-[9]aneS3 complexes with dicarboxylate ligands: synthesis, characterization and chemical behavior

With the aim of further developing the structure-activity relationship in biologically active half-sandwich Ru(ii)-[9]aneS(3) complexes ([9]aneS(3)=1,4,7-trithiacyclononane), a series of new mono- and dinuclear complexes bearing the chelating dicarboxylate ligands oxalate (ox), malonate (mal) and methylmalonate (mmal), have been synthesized and studied. Treatment of the precursor [Ru([9]aneS(3))(dmso)(3)][CF(3)SO(3)](2) (7) with equivalent amounts of K(2)(dicarb) afforded the corresponding neutral complexes with the general formula [Ru([9]aneS(3))(dmso-S)(eta(2)-dicarb)] (where dicarb=ox (1), mal (2) and mmal (3)), while using half an equivalent of K(2)(ox), the symmetric dimer [{Ru([9]aneS(3))(dmso-S)}(2)(mu-eta(4)-ox)][CF(3)SO(3)](2) (4) was isolated. The reaction of with the oxalato complex fac-[Ru(dmso-S)(3)(dmso-O)(eta(2)-ox)] (9) yielded two asymmetric dimers, namely [{Ru([9]aneS(3))(dmso-S)}(mu-eta(4)-ox){fac-Ru(dmso-S)(3)(CF(3)SO(3))}][CF(3)SO(3)] (5) and [{Ru([9]aneS(3))(dmso-S)}(mu-eta(4)-ox){fac-Ru(dmso-S)(3)(dmso-O)}][CF(3)SO(3)](2) (6), depending on the reaction conditions. All new complexes were structurally characterized, both in solution (by NMR spectroscopy) and in the solid state (by X-ray crystallography). The chemical behavior of the complexes in aqueous solution was studied by UV-Vis and NMR spectroscopy in view of their potential antitumor activity: the monomers partially release a dmso ligand to yield the monofunctional aqua adduct [Ru([9]aneS(3))(eta(2)-dicarb)(H(2)O)], while the dimers rapidly open up the oxalato bridge to give two mononuclear fragments. Splitting of the asymmetric dimers 5 and 6 occurs selectively and the ox moiety remains bonded to the fac-Ru(dmso-S)(3) fragment. A detailed comparison of the structural and chemical features of 1-6 with those of similar dicarboxylate complexes possessing the fac-Ru(dmso-S)(3) fragment in place of Ru([9]aneS(3)) allows us to draw a number of general conclusions on the binding preferences of dicarb ligands on the octahedral Ru(II) center.

Heterometallic In(III)–Pd(II) Porous Metal–Organic Framework with Square-Octahedron Topology Displaying High CO2 Uptake and Selectivity toward CH4 and N2

The targeted synthesis of metal-organic frameworks (MOFs) with open metal sites, following reticular chemistry rules, provides a straightforward methodology toward the development of advanced porous materials especially for gas storage/separation applications. Using a palladated tetracarboxylate metalloligand as a 4-connected node, we succeeded in synthesizing the first heterobimetallic In(III)/Pd(II)-based MOF with square-octahedron (soc) topology. The new MOF, formulated as [In3O(L)1.5(H2O)2Cl]·n(solv) (1), features the oxo-centered trinuclear clusters, [In3(μ3-O)(-COO)6], acting as trigonal-prismatic 6-connected nodes that linked together with the metalloligand trans-[PdCl2(PDC)2] (L4-) (PDC: pyridine-3,5-dicarboxylate) to form a 3D network. After successful activation of 1 using supercritical CO2, high-resolution microporous analysis revealed the presence of small micropores (5.8 Å) with BET area of 795 m2 g-1 and total pore volume of 0.35 cm3 g-1. The activated solid shows high gravimetric (92.3 cm3 g-1) and volumetric (120.9 cm3 cm-3) CO2 uptake at 273 K and 1 bar as well as high CO2/CH4 (15.4 for a 50:50 molar mixture) and CO2/N2 (131.7 for a 10:90 molar mixture) selectivity, with moderate Qst0 for CO2 (29.8 kJ mol-1). Slight modifications of the synthesis conditions led to the formation of a different MOF with an anionic framework, having a chemical formula [Me2NH2][In(L)]· n(solv) (2). This MOF is constructed from pseudotetrahedral, mononuclear [In(-COO)4] nodes bridged by four L4- linkers, resulting in a 3D network with PtS topology.