Effects of halide (X) and sulfoxide (R₂SO) replacement within the ruthenium(II) nitroimidazole complexes, RuX₂(R₂SO)_m, (nitroimidazole)_n, m = 1-3, n = 1 or 2: their characterization, solution chemistry, radiosensitizing activity, and related properties

Abstract

. Can. J. Chem. 67, 508 (1989).During our studies on metal-radiosensitizer complexes, a complex RuC12(dmso)2(4-N021m)2 was found to show better radiosensitizing properties and lower toxicity than the free 4-nitroimidazole ligand; complexes with N-substituted-4-nitroimidazoles were less effective as radiosensitizers (Can. J. Chem. 66, 117 (1988)). In the present study, the effects of replacement of the chloride ligand by bromide, and dimethylsulfoxide (dmso) ligand by tetramethylenesulfoxide (tmso), as well as the use of a wider variety of nitroimidazole ligands, are described. A series of ruthenium(I1) complexes of formulation: R~Cl~(dmso)~L, (L = a 2-nitroimidazole); RuCl,(tmso),,,L,, (L = a 2-or 4-nitroimidazole, m = 1-3 and n = 1 or 2); and RuBr2(dmso)'L,, (L = a 4-nitroimidazole, n = 1 or 2), has been synthesized and characterized by spectroscopic methods, particularly 'H nmr and X-ray photoelectron spectroscopy. The precursors used were RuXz(dmso),, X = C1, Br, and RuCl,(tmso),. ' The N-methyl-4-nitroimidazole (NMe-4-N021m) ligand of the complex R~Br~(dmso)~(NMe-4-NO~Im) chelates through the imidazole-N and the oxygen of NO,. Another substituted 4-nitroimidazole, R S U -3 1~9 ,~ in RuC12(tmso) (RSU-3159), binds through the sulfur and is almost certainly chelated; the complex with a substituted 2-nitroimidazole, R~Cl~(tmso)~(SR-2508), is five-coordinate and probably trigonal bipyramidal. The replacement of dmso by tmso does not markedly alter the redox properties and radiosensitizing ability of the 4-nitroimidazole complexes, but increases their lipophilicity. The tmso complexes (unlike the dmso analogues) do not bind to DNA, as evidenced by non-inhibition of restriction enzymes. The tmso/2-nitroimidazole complexes, in contrast to the dmso analogues, are stable in aqueous media. The substitution of C1-by Br-reduces the radiosensitizing ability of the 4-N021m complexes. At only 200 pM, the complexes RuC12(tmso)2(4-N021m)2 and R~Cl~(tmso)~(SR-2508) have promising sensitizing enhancement ratio values of 1.6 and 1.5, respectively, and require further biological assessment.Key words: ruthenium, nitroimidazoles, sulfoxides, radiosensitizers. Un autre nitro-4 imidazole substitue, le RSU-3159~ que l'on retrouve dans le complexe RuCl,(tmso) (RSU-3 159), se complexe par le soufre et est vraisemblablement chelate; le complexe issu d'un nitro-2 imidazole substituC, le R~Cl~(tmso)~(SR-2508), est pentacoordonnC et est probablement du type trigonal bipyramidal. Le remplacement du dmso par le tmso n'influence pratiquement pas les proprietCs redox et radiosensibilisatrices des complexes nitro-4 irnidazoles; toutefois, ces substitutions augmentent leurs propriCtCs lipophiles. Tel qu'on a pu le demontrer par le fait qu'ils n'inhibent pas les enzymes de restriction, les complexes du tmso (contrairement i leurs analogues dmso) ne se lient pas 2 I'ADN. Par opposition 2 leurs analogues du dmso, les complexes du tmso/nitro-2 imidazole sont stables en solutions aqueuses. La substitution d'un C1-par un Br-rCduit les propriCtCs radio...

Ruthenium(II) Sulfoxide−Maltolato and −Nitroimidazole Complexes: Synthesis and MTT Assay

“…These data are consistent with the presence of the three cis isomers, the inequivalent ma ligands in C giving rise to two Me singlets and the equivalent Me groups in D and E each giving rise to one; the doublets are assigned similarly to H (5) and H (6). The 12 singlets between δ 2.7 and 3.4 correspond to the Me groups of the S-bonded DMSO ligands. , The formation of the trans isomers ( A and B ), which like D and E also have equivalent ma ligands, is not favored because the π-accepting sulfoxides would prefer when possible not to be mutually trans . Our interpretation of the 1 H NMR spectrum agrees with that discussed in an M.Sc.…”

“…Complexes 1a and 2a . The solid-state molecular structure of 1a was reported 19 to be a cis isomer with S-bonded DMSO ligands (structure C in Chart ; the IR ν S  O value, 39 cm -1 > that of 1055 cm -1 for free DMSO, supports solely S-bonded sulfoxide , ), but the solution structure is more complex. , Because of the inequivalence of the O atoms of the maltolato (ma) ligand, three cis and two trans stereoisomers are possible for the solely S-bonded sulfoxide species 1a (and 2a ) (Chart ). The 1 H NMR spectrum of 1a in C 6 D 6 exhibits four singlets in the δ 2.1 region, each assignable to a Me of ma, while two sets of four doublets centered at ∼ δ 6.1 and 6.5 are assigned to the ma H (5) and H (6), respectively.…”

“…Our group was the first to synthesize cis- RuCl 2 (DMSO) 4 but for use as an olefin hydrogenation catalyst, this then leading to the first chiral sulfoxide systems for asymmetric hydrogenation . We later synthesized Ru II sulfoxide−nitroimidazole complexes as potential radiosensitizers, with RuCl 2 (DMSO) 2 (4-NO 2 Im) 2 being the most effective, although the configuration of such complexes was never established by a crystal structure . Bidentate-sulfoxide complexes of the type cis- or trans- RuCl 2 (S−S) 2 , where S−S = sulfur-bonded RS(O)(CH 2 ) n S(O)R (R = alkyl or aryl), were then made, and in vitro assays indicated that they accumulated in Chinese hamster ovary cells without hypoxic selectivity or toxicity, while the trans species accumulated in DNA to a greater degree than the cis complexes. , …”

Metal Complexes as Photo- and Radiosensitizers

“…Introduction of an imidazole group to yield a trans -[RuCl 4 (Im) 2 ] 2- complex ( 317 ) increases the electron affinity of the ligand resulting in stronger radiosensitizing properties . A series of Ru(II) complexes of formula RuCl 2 (DMSO) 2 L n , where DMSO = S-bonded DMSO and L = a 4-NO 2 Im derivative such as 4-NO 2 Im ( 318 ), RSU-1170 ( 323 ), RSU-3083 ( 320 ), and RSU-3100 ( 321 ), NMe-4-NO 2 −Im ( 319 ), and 1-Me-5-(2‘-thioimidazolyl)-4-NO 2 Im ( 324 , RSU-3159), or a 2-NO 2 Im derivative of misonidazole ( 285 ) and desmethylmisonidazole ( 325 ), were obtained from the precursor complex cis -RuCl 2 (DMSO) 4 by substitution of two sulfoxide ligands . The spectral data (XPS, 1 H NMR or IR) showed that the diamagnetic, hexacoordinated complexes have a cis structure (i.e., cis, cis, cis), with both DMSO ligands being S-bonded.…”

Bidentate Sulfoxide Complexes of Ruthenium(II) and Their Preliminary Biological Assessment in Vitro

“…The potential for using new sulfoxide complexes of Ru as anticancer agents is an intriguing one, following reports on the antitumor activity of cis- and trans- RuCl 2 (DMSO) 4 , , and other Ru(III)−DMSO species (DMSO = dimethyl sulfoxide). Our group has been interested in ruthenium−sulfoxide complexes, initially as catalysts for homogeneous hydrogenations of olefins and later as precursors to transition metal-based radiosensitizers, the goal being to synthesize Ru−sulfoxide−nitroimidazole complexes. We have shown that the radiosensitizing abilities of certain 2- and 4-nitroimidazoles are improved upon coordination to Ru(II) 6 using cis -RuCl 2 (DMSO) 4 and cis -RuCl 2 (TMSO) 4 as precursors 5 (TMSO = tetramethylene sulfoxide).…”