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

Abstract

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.