In vitro Ruthenation of Human Breast Cancer Suppressor Gene 1 (BRCA1) by the Antimetastasis Compound RAPTA-C and Its Analogue CarboRAPTA-C

The interaction of two ruthenium-arene-1,3,5-triaza-7-phosphaadamantane compds. ([Ru(η6-p-cymene)Cl2(pta)] and [Ru(η6-p-cymene)(C6H6O4)(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, crosslinking, base specificity, restriction anal., and in vitro inhibition of DNA polymn. 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 compds. Moreover, the rate of DNA interaction for 3 is in a similar range to that of 2, despite the fact that these compds. have a different therapeutic profile. The similar rates of reaction contrasting with the different modes of activity suggests that the RAPTA compds. may be clin. useful against cancer cells that have developed resistance to Pt-based therapies, particularly involving excision-repair mechanisms.