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Open AccessArticle

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

1
Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Mie 513-8670, Japan
2
Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan
*
Author to whom correspondence should be addressed.
Inorganics 2019, 7(1), 5; https://doi.org/10.3390/inorganics7010005
Received: 7 November 2018 / Revised: 18 December 2018 / Accepted: 24 December 2018 / Published: 8 January 2019
Tetrazolato-bridged dinuclear platinum(II) complexes ([{cis-Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)]2+; tetrazolato-bridged complexes) are a promising source of next-generation platinum-based drugs. β-Cyclodextrin (β-CD) forms inclusion complexes with bulky organic compounds or substituents, changing their polarity and molecular dimensions. Here, we determined by 1H-NMR spectroscopy, the stability constants for inclusion complexes formed between β-CD and tetrazolato-bridged complexes with a bulky, lipophilic substituent at tetrazole C5 (complexes 13, phenyl, n-nonyl, and adamantyl substitution, respectively). We then determined the in vitro cytotoxicity and in vivo antitumor efficacy of complexes 13 against the Colon-26 colorectal cancer cell line in the absence or presence of equimolar β-CD. Compared with the platinum-based anticancer drug oxaliplatin (1R,2R-diaminocyclohexane)oxalatoplatinum(II)), complex 2 had similar cytotoxicity, complex 3 was moderately cytotoxic, and complex 1 was the least cytotoxic. The cytotoxicity of the complexes decreased in the presence of β-CD. When we examined the in vivo antitumor efficacy of complexes 13 (10 mg/kg) against homografted Colon-26 colorectal tumors in male BALB/c mice, they showed a relatively low tumor growth inhibition compared with oxaliplatin. However, in the presence of β-CD, complex 3 had higher in vivo antitumor efficacy than oxaliplatin, suggesting a new direction for future research into tetrazolato-bridged complexes with high in vivo antitumor activity. View Full-Text
Keywords: anticancer drug; cancer; cyclodextrin; drug discovery; platinum anticancer drug; cancer; cyclodextrin; drug discovery; platinum
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Komeda, S.; Uemura, M.; Yoneyama, H.; Harusawa, S.; Hiramoto, K. In Vitro Cytotoxicity and In Vivo Antitumor Efficacy of Tetrazolato-Bridged Dinuclear Platinum(II) Complexes with a Bulky Substituent at Tetrazole C5. Inorganics 2019, 7, 5.

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