Mechanism of Cytotoxicity and Cellular Uptake of Lipophilic Inert Dinuclear Polypyridylruthenium(II) Complexes

Abstract

The accumulation, uptake mechanism, cytotoxicity, cellular localisation of-and mode of cell death induced by-dinuclear ruthenium(II) complexes ΔΔ/ΛΛ-[{Ru(phen)(2) }(2) {μ-bb(n) }](4+) (Rubb(n)), where phen is 1,10-phenanthroline, bb(n) is bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n=2, 5, 7, 10, 12 or 16), and the corresponding mononuclear complexes containing the bb(n) ligands, were studied in L1210 murine leukaemia cells. Cytotoxicity increased with linker chain length, and the ΔΔ-Rubb(16) complex displayed the highest cytotoxicity of the series, with an IC(50) value of 5 μM, similar to that of carboplatin in the L1210 murine leukaemia cell line. Confocal microscopy and flow cytometry studies indicated that the complexes accumulate in the mitochondria of L1210 cells, with the magnitude of cellular uptake and accumulation increasing with linking chain length in the bb(n) bridge of the metal complex. ΔΔ-Rubb(16) entered the L1210 cells by passive diffusion (with a minor contribution from protein-mediated active transport), inducing cell death via apoptosis. Additionally, metal-complex uptake in leukaemia cells was approximately 16-times that observed in healthy B cells highlighting that the bb(n) series of complexes may have potential as selective anticancer drugs.

Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates

“…164 The in cancer cells. 169 Further studies revealed that the introduction of polyether or polyamine in the linking chains lowered the cytotoxicity, while the trinuclear and tetranuclear species exerted higher activity when compared with their dinuclear analogues. 170 Moreover, this class of complexes showed interesting results as potential antimicrobial agents.…”

“…The mechanism exhibits a multistep pathway by in Figure 28). [168,169] They demonstrated that increasing the lipophilicity of the complexes by increasing the length of the alkane chain significantly improved the cytotoxic properties. 168 The cytotoxicity of this family of Ru(II) complexes was analysed in the L1210 cell line.…”

Polypyridyl Metal Complexes with Biological Activity

“…DNA binding does not correlate with the biological activity; nevertheless, it is possible that interaction with mitochondrial DNA can inhibit mitochondrial activity. [36] Derivatives in which the alkane chain is substituted by a polyether or polyamine residue present lower cytotoxicity.…”

“…Also, it is found that the ΔΔ enantiomer in the case of 26 n=16 is more active than the ΛΛ; however, such a trend is less clear in the case of other chain lengths, where the differences are less pronounced. [36] Uptake into L1210 and isolated B cells was assayed for 26 n=16 by flow cytometry at different concentrations according to its IC 50 values. Compound ΔΔ-26 n=16 showed a high level of uptake in L1210 as compared to other complexes.…”

Differential Anticancer Activities of the Geometric Isomers of Dinuclear Iridium(III) Complexes

“…[11][12][13][14][15] Inert ruthenium(II) complexes generally target DNA, e.g. as metallointercalators, although other mechanism of action have been proposed.…”