Azolato-bridged dinuclear platinum(II) complexes exhibit remarkable antitumor efficacy in vivo

Abstract Platinum-based drugs (Pt-drugs), such as cisplatin, are essential chemotherapeutic agents that exhibit strong tumor-reducing effects against a wide range of cancers. Their success has greatly stimulated cancer research in the field of inorganic biochemistry. However, the current consensus is that cisplatin derivatives with closely related structures do not offer sufficient clinical advantages to replace existing Pt-drugs. In particular, the next-generation of Pt-drugs are expected to be effective against cancers that are resistant or insensitive to standard treatments. Therefore, there is a need to design platinum complexes with fundamentally different structures. Based on this goal, our group has designed and investigated a series of azolato-bridged dinuclear platinum (II) complexes, cis-Pt (NH3) 2µ-OH) (µ-azolato) Xn (where azolato = pyrazolato, 1, 2, 3-triazolato, or tetrazolato; X = NO3 or ClO4; and n = 1 or 2), that have unique mechanisms of action and in vivo antitumor efficacy. Promising compounds in this series are represented by the general formula cis-Pt (NH3) 22 (µ-OH) (µ-5-R-tetrazolato-N2, N3) Xn and were derived using tetrazoles with various substituents (R) at the tetrazole C5 position. Notably, both antitumor efficacy and toxicity varies markedly depending on the substituent. This review summarizes the unique mechanisms of action and structure–activity relationships of these complexes based on in vitro and in vivo studies.