Although Pt-containing drugs such as cisplatin are excellent anticancer agents in clinical use, such drugs have severe side effects; in addition, the existence of cisplatin-resistant strains has been reported. [[1], [2], [3]] Cisplatin interacts with DNA, coordinating especially with guanine. [[4], [5], [6]] The coordination of cisplatin to DNA substantially distorts the DNA structure, leading to impaired DNA repair and the induction of apoptosis. [3] However, such covalent DNA damage is also often efficiently recognized and repaired by cellular repair enzymes, thereby contributes to the development of cisplatin resistance. [1] Therefore, it is important to develop anticancer metal complexes that exhibit modes of interaction with DNA different from those of cisplatin.

We have focused on Pt(II) and Pd(II) complexes with anticancer activity. Although Pd(II) and Pt(II) belong to the same group, Pd(II) complexes are generally more labile than Pt(II) complexes. [7] Pd(II) complexes have generally been considered less suitable as anticancer drugs than Pt(II) complexes because many of them tend to undergo rapid ligand exchange and decomposition in vivo. [8] However, Pd(II) complexes with bidentate and tridentate ligands have been reported to exhibit sufficient structural and kinetic stability in biological environments, making Pd(II) complexes promising candidates for anticancer drugs. For example, Yilmaz and co-workers reported that a Pd complex with a tridentate ligand, terpyridine (terpy), [Pd(sac)(terpy)](sac)·4H2O (terpy = 2,2′:6′,2″-terpyridine, sac = saccharinate), exhibits superior anticancer activity compared with cisplatin both in vivo and in vitro. [[9], [10], [11]] We synthesized Pt(II) and Pd(II) complexes with terpy ligands and investigated their anticancer activity. The Pd(II) complexes were found to exhibit strong anticancer activity. [12]

In this study, we focused on Pt(II) and Pd(II) complexes bearing dipyrido[3,2-a:2′,3′-c]phenazine (dppz) and 10,11,12,13-tetrahydrodipyrido[3,2-a:2′,3′-c]phenazine (thdppz), which are ligands known for their DNA-intercalating properties.

In particular, many metal complexes bearing dppz ligands have been synthesized and shown to act as efficient DNA intercalators. Moreover, numerous Ru–dppz complexes have been reported to exhibit unique photochemical properties as well as strong interactions with DNA. [[13], [14], [15], [16]] Furthermore, extensive studies have investigated the DNA interactions of hexacoordinate octahedral complexes containing dppz ligands, including those of Os(III) [[17], [18], [19]], Re(I) [[20], [21], [22]], Ir(III) [21,23,24], Fe(II) [25], Mo(0) [26], Co(III) [27,28]. In addition, while numerous reports on Pt complexes with dppz ligands have appeared in the literature [[29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40]], only a few Pd complexes with dppz ligands have been synthesized [[41], [42], [43], [44], [45]], and reports on their anticancer activity are very limited. [43,45]

Because dppz is a highly planar ligand, metal complexes containing dppz ligands, especially those without any charge, exhibit extremely low solubility. Therefore, in the present study, we focused on [Pt(dppz)(py)2]2+ [33], in which pyridine (py) ligands are coordinated to the Pt–dppz core in order to improve solubility. On the basis of this Pt complex, we synthesized [Pd(dppz)(py)2]2+ and evaluated its anticancer activity to directly compare the anticancer activities of metal centers within the same ligand system (Fig. 1). Furthermore, although thdppz has a lower intercalative ability than dppz, we also synthesized [Pt(thdppz)(py)2]2+ and [Pd(thdppz)(py)2]2+ complexes, which contain the thdppz ligand where the terminal aromatic ring of dppz is replaced by a cyclohexane ring. Using [Pt(dppz)(py)2]2+, which is regarded as an intercalative DNA binder, as a reference, we investigated the cytotoxicity of [Pd(dppz)(py)2]2+ and [Pd(thdppz)(py)2]2+. On the basis of their kinetic lability, these Pd(II) complexes are expected, based on their kinetic lability, to form coordinate covalent bonds with DNA.

This study aims to clarify the differences in interactions between Pt and Pd complexes with DNA and biomolecules such as serum albumin, thereby providing new guidelines for the design of anticancer metal complexes with mechanisms distinct from those of platinum-based drugs.