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.

Cellular responses of BRCA1-defective and triple-negative breast cancer cells and in vitro BRCA1 interactions induced by metallo-intercalator ruthenium(II) complexes containing chloro-substituted phenylazopyridine

“…Platinum drugs exert their antitumor effects by binding to DNA, thereby changing the replication of DNA and inhibiting the growth of the tumor cells. For ruthenium-based drugs, there has been some evidence demonstrating an interaction between ruthenium complexes and DNAs [18,20,30]. Our previous study has demonstrated that 1 and 2 bound to the specified DNA fragment of the human breast cancer suppressor gene 1 (BRCA1) through the intercalative mode into the base pairs of DNA, and the DNA-binding constants (K b ) for 1 and 2 were 7.09 × 10 4 M -1 and 5.19 × 10 5 M -1 , respectively.…”

The development of RAPTA compounds for the treatment of tumors

“…In the cisplatin-resistant cell line this preference is reduced and shifted towards the nucleus and cytosol [98]. A c c e p t e d M a n u s c r i p t 65 The nature of interactions of RAPTA-C and carbo-RAPTA-C ( Figure 19, (49)) with the DNA sequence of the human breast cancer suppressor gene 1 (BRCA1) was investigated using conformational analysis of ruthenated DNA, crosslinking assays and semi-quantitative PCR [104]. In accordance with the results described above ruthenation induced unwinding of the supercoiled DNA.…”

Organometallic ruthenium-based antitumor compounds with novel modes of action

“…The calculation also revealed that the arene ring of 2 does not interfere with WatsonCrick base-pairing of adjacent bases nor intercalate between basepairs, which is different from [(h 6 -p-cymene)Ru(en)Cl] þ . Since these simulations suggest 2 forms DNA adducts akin to that of cisplatin, a study into the nature of ruthenated DNA lesion was undertaken using conformational analysis of ruthenated DNA, interstrand crosslinks assays and semi-quantitative PCR [51]. Restriction analysis indicated that 2 preferentially binds at purine sites and that the lesions are capable to inhibiting DNA polymerization.…”