Structure-activity relationships for ruthenium(II)-arene drugs

The discovery of the anticancer properties of cisplatin in 1965 heralded the development of metallopharmaceuticals and founded a revolution in cancer therapy. Platinum drugs are believed to induce cytotoxicity by cross-linking DNA, causing changes to the DNA structure that inhibit replication and protein synthesis. Many current inorganic drugs such as cisplatin and related compounds are successfully used in the treatment of many cancer types. However there are problems associated with their use, in particular, cisplatin is highly toxic, leading to side effects and limiting the dose that can be administered. Complexes based on other metals have been investigated for their possible application as antitumour drugs. One of the most promising metals is ruthenium, and a number of ruthenium complexes show high in vitro and in vivo antitumour activity and some compounds are currently undergoing clinical trials. Organometallic ruthenium(II)-arene PTA complexes (PTA = 1,3,5-triaza-7-phosphaadamantane) with the general formula, RuCl2(η6-arene)(PTA) abbreviated RAPTA, were developed as part of this PhD thesis. These new compounds were characterised and evaluated for their in vitro anticancer activity towards the TS/A mouse adenocarcinoma and the healthy HBL-100 human mammary cell lines. Selective activity of RAPTA compounds towards tumour cells was observed. The p-cymene and benzene compounds RAPTA-C and RAPTA-B respectively, were selected for in vivo evaluation of their anticancer and antimetastatic activity and they were shown to be able to reduce the growth of lung metastases in CBA mice bearing the MCa mammary carcinoma. Moreover, a pharmacokinetic study of RAPTA-C was carried out to examine the fate of the compound in vivo after administration. Extending the series of RAPTA anticancer drugs, novel structurally modified RAPTA compounds were developed exploiting different strategies for establishing structure-activity relationships. The efficacy on enhancing the activity, the uptake and the biomolecular interactions of the novel drugs was evaluated and the effectiveness was compared to the non-functionalised RAPTA series of complexes.