The discovery of new metal-based antitumour drugs, whether cisplatin derivatives or those based on other metals, has been largely based on cell viability assays (IC₅₀ values) and compounds that bind to DNA. This approach has been applied for more than 30 years during which time very few new drugs have entered clinical use. In this article we discuss what the future holds for metal-based drugs, in particular anti-metastasis drugs, in these enlightened times of the post genomic era.

NAMI-A, i. e. (imH)[trans-RuCl4(dmso-S)(im)] (im = imidazole, dmso = dimethylsulfoxide), is a Ru(III) complex that, after extensive preclinical investigations that evidenced its remarkable and specific activity against metastases, has recently and successfully completed a Phase I trial (first ruthenium complex ever to reach clinical testing). This review article, after a brief summary of the main chemical and pharmacological aspects of NAMI-A, focuses on the development of new classes of ruthenium complexes originated from the NAMI-A frame. In particular, the chemical and biological features of the following classes of compounds will be treated: i) NAMI-A-type complexes, derived from NAMI-A by changing the nature of the N-ligand, ii) dinuclear NAMI-A-type compounds containing heterocyclic bridging N-N ligands, iii) new Ru-dmso nitrosyls broadly derived from NAMI-A-type complexes. Several of these new compounds were found to have antimetastatic activity comparable to, or even better than, NAMI-A; however, the nature of the target(s) responsible for the antimetastatic activity remains unclear. Common to any type of NAMI-A-type compound, both monomeric and dimeric, cell cytotoxicity (which is generally very low) is not sufficient to explain their potent and peculiar antitumor activity. All active NAMI-A-type compounds share the capacity to modify important parameters of metastasis such as tumor invasion, matrix metallo proteinases activity and cell cycle progression.

Ruthenium anticancer drugs have attracted an increasing interest in the last 20 years and two of them have entered clinical trials. Compared to platinum drugs, the complexes based on ruthenium are often identified as less toxic and capable of overcoming the resistance induced by platinum drugs in cancer cells. These activities were attributed to the transportation to tumour cells by transferrin and to the selective activation to more reactive species by the reducing environment of solid tumours as compared to healthy tissues. Ruthenium anticancer drugs have been almost always designed to mimic platinum drugs, particularly for targeting DNA. Indeed, none of the above properties has never been clearly demonstrated even for the ruthenium drugs that entered clinical trials. The suggestion for the future is to change the perspective when designing new chemical entities, abandoning the philosophy that guided the actual panel of ruthenium drugs and to look further into the fine mechanism by which the most relevant ruthenium complexes available kill the target tumour cells, then focusing on targets selective of tumour cells and responsible for cell growth and malignancy.