Specific Conformational Change in Giant DNA Caused by Anticancer Tetrazolato-Bridged Dinuclear Platinum(II) Complexes: Middle-Length Alkyl Substituents Exhibit Minimum Effect

Abstract

Derivatives of the highly antitumor-active compound [{cis-Pt(NH)}(μ-OH)(μ-tetrazolato-N2,N3)] (5-H-Y), which is a tetrazolato-bridged dinuclear platinum(II) complex, were prepared by substituting a linear alkyl chain moiety at C5 of the tetrazolate ring. The general formula for the derivatives is [{cis-Pt(NH)}(μ-OH)(μ-5-R-tetrazolato-N2,N3)], where R is (CH)CH and n = 0 to 8 (complexes 1-9). The cytotoxicity of complexes 1-4 in NCI-H460 human non-small-cell lung cancer cells decreased with increasing alkyl chain length, and those of complexes 5-9 increased with increasing alkyl chain length. That is, the in vitro cytotoxicity of complexes 1-9 was found to have a U-shaped association with alkyl chain length. This U-shaped association is attributable to the degree of intracellular accumulation. Although circular dichroism spectroscopic measurement indicated that complexes 1-9 induced comparable conformational changes in the secondary structure of DNA, the tetrazolato-bridged complexes induced different degrees of DNA compaction as revealed by a single DNA measurement with fluorescence microsopy, which also had a U-shaped association with alkyl chain length that matched the association observed for cytotoxicity. Complexes 7-9, which had alkyl chains long enough to confer surfactant-like properties to the complex, induced DNA compaction 20 or 1000 times more efficiently than 5-H-Y or spermidine. A single DNA measurement with transmission electron microscopy revealed that complex 8 formed large spherical self-assembled structures that induced DNA compaction with extremely high efficiency. This result suggests that these structures may play a role in the DNA compaction that was induced by the complexes with the longer alkyl chains. The derivatization with a linear alkyl chain produced a series of complexes with unique cellular accumulation and DNA conformational change profiles and a potentially useful means of developing next-generation platinum-based anticancer drugs. In addition, the markedly high ability of these complexes to induce DNA compaction and their high intracellular accumulation emphasized the difference in mechanism of action from platinum-based anticancer drugs.

Anticancer platinum‐based complexes with non‐classical structures

“…These findings suggest that tetrazolato‐bridged dinuclear Pt(II) complexes, especially 7 , have the potential to become a basic skeleton for the next generation of antitumor drugs that can solve drug resistance of classical platinum drugs because of novel mechanisms. Komeda and co‐workers have made a thorough investigation to determine the mechanism of 7 and its derivatives (complexes 8 – 16 ; Figure ) . They found a U‐shaped association between alkyl chain length and cytotoxicity, where cytotoxicity decreased with increasing alkyl chain length up to an alkyl chain length of four or five, which agrees with the previous finding that this class of Pt(II) complexes with a bulky substituent at C5 are generally less cytotoxic than those with a small substituent.…”

Different Effects of Cisplatin and Transplatin on the Higher-Order Structure of DNA and Gene Expression

“…Using fluorescence microscopy (FM) and atomic force microscopy (AFM), we elucidated the higher-order conformational changes of single long DNA strings induced by some novel cationic dinuclear Pt(II) complexes [29][30][31], which are potent anticancer drug candidates [32]. We found that these complexes shrink DNA much more efficiently than cisplatin.…”

In Vitro Cytotoxicity and In Vivo Antitumor Efficacy of Tetrazolato-Bridged Dinuclear Platinum(II) Complexes with a Bulky Substituent at Tetrazole C5

“…Comparable results were obtained for cytotoxicity against L1210 murine leukemia cell lines [35]. Therefore, the introduction of bulky substituents tended to produce a lower in vitro cytotoxicity, possibly because the DNA interaction mode and cellular accumulation of complex 1 and 2 are distinct from those of 5-H-Y, and from other derivatives with a relatively small substituent at tetrazole C5 [34,45]. The cytotoxicity of oxaliplatin and complex 3 was markedly decreased in the presence of equimolar β-CD, whereas the cytotoxicity of 5-H-Y and complex 2 remained largely unchanged.…”

“…Tetrazolato-bridged complexes with the formula [{cis-Pt(NH 3 ) 2 } 2 (µ-OH)(µ-5-R-tetrazolato-N2,N3)] (NO 3 ) 2 (complexes 1-3, 5-H-Y) were prepared using previously reported methods [13,31,34,35]. Oxaliplatin and β-CD were purchased from Tokyo Chemical Industry (Tokyo, Japan) and Wako Pure Chemical (Osaka, Japan), respectively.…”

“…These complexes consist of two Pt(II) coordination spheres bridged by azolato and hydroxo anions, the latter of which acts as a leaving group, enabling bifunctional covalent binding to DNA. Due to their positive charges, these complexes have multimodal DNA binding modes [29,30], a characteristic that makes these series of complexes cytotoxic in many human tumor cell lines and circumvents the cross-resistance to cisplatin [31][32][33][34].…”