Study of Ruthenium(II) Complexes with Anticancer Drugs as Ligands. Design of Metal-Based Phototherapeutic Agents

Abstract

The reaction of trans-[RuCl(2)(PPh(3))(3)] (Ph = C(6)H(5)) with 2-thio-1,3-pyrimidine (HTPYM) and 6-thiopurines (TPs) produced mainly crystalline solids that consist of cis,cis,trans-[Ru(PPh(3))(2)(N,S-TPYM)(2)] (1) and cis,cis,trans-[Ru(PPh(3))(2)(N(7),S-TPs)(2)]X(2) (X = Cl(-), CF(3)SO(3)(-)). In the case of TPs, other coordination isomers have never been isolated and reported. Instead, the mother liquor obtained after filtration of 1 produced red single crystals of trans,cis,cis-[Ru(PPh(3))(2)(N,S-TPYM)(2)].2H(3)O(+).2Cl(-) (2.2H(3)O(+).2Cl(-)). Selected ruthenium(II)-thiobase complexes were studied for their structural, reactivity, spectroscopic, redox, and cytotoxic properties. Single crystals of 1 contain thiopyrimidinato anions chelated to the metal center via N and S. The Ru[bond]N bonds are significantly elongated for 1 [2.122(2) and 2.167(2) A] with respect to 2 [2.063(3) A] because of the trans influence from PPh(3). The coordination pseudo-octahedron for 2 is significantly elongated at the apical sites (PPh(3) ligands). Solutions of cis,cis,trans isomers in air are stable for weeks, whereas those of 2 turn green within 24 h, in agreement with the respective redox potentials. cis,cis,trans- and trans,cis,cis-[Ru(PH(3))(2)(N,S-TPYM)(2)], as optimized through the DFT methods at the Becke3LYP level are in good agreement with experimental geometrical parameters (1 and 2), with cis,cis,trans being more stable than trans,cis,cis by 3.88 kcal. The trend is confirmed by molecular modeling based on semiempirical (ZINDO/1) and molecular mechanics (MM) methods. Cytotoxic activity measurements for cis,cis,trans-[Ru(PPh(3))(N-THZ)(N(7),S -H(2)TP)(2)]Cl(2) (4) (THZ = thiazole, H(2)TP = 6-thiopurine) and cis,cis,trans-[Ru(PPh(3))(2)(N(7),S-HTPR)2]Cl(2) (5) (HTPR = 6-thiopurine riboside) against ovarian cancer cells A2780/S gave IC(50) values of 17 +/- 1 and 29 +/- 9 microM, respectively. Furthermore, the spectral analysis of HTPYM, TPs, and their Ru(II) complexes in solution shows that intense absorptions occur in the UVA/vis region of light, whereas standard nucleobases absorb in the UVB region.

RuII Complexes Incorporating Tetrathiamacrocycles: Synthesis and Conformational Analysis

“…Previously, density functional theory (DFT) calculations have provided relevant information concerning the structure and energetics of macrocyclic and thio complexes. [28] In order to rationalize the conformational preferences of the [n]ane-S 4 …”

New platinum–oxicam complexes as anti-cancer drugs. Synthesis, characterization, release studies from smart hydrogels, evaluation of reactivity with selected proteins and cytotoxic activity in vitro

“…The method often used by some of the authors of this paper in order to contribute to point (a) consisted in linking active drugs to metal ions from the platinum group and copper in case anti-cancer and anti-rheumatic activities were sought [13][14][15][16]. The rationale was that the ligands and the metal might have synergistic beneficial effects once the coordination molecule dissociates inside the living cell.…”

Synthesis and characterization of nitrosyl complexes containing 4,6-dimethyl-pyrimidine-2-thiolato (‘SpymMe2’) as ligand: [Ru(‘SpymMe2’,-N,-S) (‘SpymMe2’,-S)(NO)(P–P)](PF6) (P–P=1,2-bis(diphenylphosphino)ethane or 1,2-bis(diphenylphosphino)ethylene

“…Since the discovery of the biological roles of NO [2] and its complexes with heme and non-heme iron proteins [2,3], a renewed interest in the chemistry of ruthenium nitrosyls appeared among inorganic chemists [4][5][6]. Ligands of the thiopyrimidines type and their complexes are currently being investigated as antiviral, antimetabolite and antitumor drugs as well as for their interesting photochemical properties [7][8][9]. These ligands are ubiquitous S, N donors that form a wide variety of complexes with different kind of metals.…”