Recent developments in ruthenium anticancer drugs.

Interest in Ru anticancer drugs has been growing rapidly since NAMI-A ((ImH(+))[Ru(III)Cl(4)(Im)(S-dmso)], where Im = imidazole and S-dmso = S-bound dimethylsulfoxide) or KP1019 ((IndH(+))[Ru(III)Cl(4)(Ind)(2)], where Ind = indazole) have successfully completed phase I clinical trials and an array of other Ru complexes have shown promise for future development. Herein, the recent literature is reviewed critically to ascertain likely mechanisms of action of Ru-based anticancer drugs, with the emphasis on their reactions with biological media. The most likely interactions of Ru complexes are with: (i) albumin and transferrin in blood plasma, the former serving as a Ru depot, and the latter possibly providing active transport of Ru into cells; (ii) collagens of the extracellular matrix and actins on the cell surface, which are likely to be involved in the specific anti-metastatic action of Ru complexes; (iii) regulatory enzymes within the cell membrane and/or in the cytoplasm; and (iv) DNA in the cell nucleus.

A potential role for protein tyrosine phosphatase inhibition by a RuIII-edta complex (edta = ethylenediaminetetraacetate) in its biological activity.

[RuIII(edta)(OH2/OH)]1-/2- (edta = ethylenediaminetetraacetate) inhibits protein tyrosine phosphatase (PTP) at physiological pH values in a mechanism that involves binding of the Cys residue of the catalytic domain of the enzyme and similar interactions may be important in the anti-cancer properties of the active forms of many Ru pro-drugs.

Reaction of [RuIII(edta)(H2O)]- with H2O2 in aqueous solution. Kinetic and mechanistic investigation.

The reaction of [Ru(III)(edta)(H(2)O)](-) (1) (edta = ethylenediaminetetraacetate) with hydrogen peroxide was studied kinetically as a function of [H(2)O(2)], temperature (5-35 degrees C) and pressure (1-1300 atm) at a fixed pH of 5.1 using stopped-flow techniques. The reaction was found to consist of two steps involving the rapid formation of a [Ru(III)(edta)(OOH)](2-) intermediate which subsequently undergoes parallel heterolytic and homolytic cleavage to produce [(edta)Ru(V)=O](-) (45%) and [(edta)Ru(IV)(OH)](-) (55%), respectively.

Kinetics and mechanism of the reaction of [RuIII(edta)(H2O)]- with HOBr to form an intermediate RuV=O complex in aqueous solution.

The interaction of [Ru(III)(edta)(H(2)O)](-) (1) (edta = ethylenediaminetetraacetate) with the oxygen transfer agent HOBr, was studied kinetically as a function of [HOBr] and temperature (5-35 degrees C) at a fixed pH of 6.2. Spectroscopic evidence is reported for the formation of a high valent intermediate (edta)Ru(V)=O complex.