Metal complexes with aromatic N-containing ligands as potential agents in cancer treatment

Cisplatin (cis-Diamminedichloroplatinum(II)) is now clinically used as one of the most effective anticancer drugs in the treatment of a variety of human solid tumors, such as genitourinary. Unfortunately, its usefulness is limited due to development of resistance in tumor cells and its significant side effects. Thus, a continuing effort is being made to develop analogs to overcome the above shortcomings. However, direct structural analogs of cisplatin have not shown greatly improved clinical efficacy in comparison with the parent drug. The explanation for this finding is that all cis-[PtX(2)(amine)(2)] compounds have shown similar DNA-binding modes, thereby resulting in similar biological consequences. One approach is to look beyond structure-activity on the basis of cisplatin analogs antitumor agents, by identifying novel materials that can be utilized as building blocks. These may have DNA binding modes quite different from that of cisplatin. The introduction of such aromatic N-containing ligands as pyridine, imidazole and 1,10-phenanthroline, and their derivatives (whose donor properties are somewhat similar to the purine and pyrimidine bases) to antitumor agents is drawing attention. Many platinum and non-platinum metal complexes such as palladium, ruthenium, rhodium, copper, and lanthanum, with these aromatic N-containing ligands, have shown very promising antitumor properties in vitro and in vivo in cisplatin-resistant model systems or against cisplatin-insensitive cell lines. For example, one Ru(III) compound, [ImH][trans-Cl(4)(Me(2)SO)(Im)Ru(III)] (Im = imidazole, NAMI-A) successfully entered phase I clinical trials. In this review, medicinal chemistry, DNA binding modes, and the development status of these metal complexes are discussed.