The interaction of two ruthenium-arene-1,3,5-triaza-7-phosphaadamantane compounds ([Ru(eta(6)-
p-cymene)Cl(2)(pta)] and [Ru(eta(6)-
p-cymene)(C(6)H(6)O(4))(pta)], termed
RAPTA-C (3) and carboRAPTA-C (4), resp.) with the DNA sequence of the human
breast-cancer suppressor gene 1 (BRCA1) has been studied using a range of techniques that probe conformation, cross-linking, base specificity, restriction analysis, and in vitro inhibition of
DNA polymerization. The study demonstrates that substitution of the two labile
chloride ligands in 3 by the more stable cyclobutane-1,1-dicarboxylate
ligand onto the RAPTA framework reduces the rate of reaction with
DNA in a similar manner to the analogous Pt-based
drug pair
cisplatin (1) and
carboplatin (2), suggesting that hydrolysis may be a prerequisite to
DNA binding with the Ru compounds. Moreover, the rate of
DNA interaction for 3 is in a similar range to that of 2, despite the fact that these compounds have a different therapeutic profile. The similar rates of reaction contrasting with the different modes of activity suggests that the RAPTA compounds may be clinically useful against
cancer cells that have developed resistance to Pt-based
therapies, particularly involving excision-repair mechanisms.