Development of next-generation anticancer drugs using dinuclear transition metal complexes

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590063
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: Suzuka University of Medical Science
• Principal Investigator: KOMEDA Seiji 鈴鹿医療科学大学, 薬学部, 准教授 (60425056)
• Co-Investigator(Kenkyū-buntansha): UEMURA Masako 鈴鹿医療科学大学, 薬学部, 助手 (70511997)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 制がん剤 / 白金 / DNA / 薬物耐性 / 金属錯体

Outline of Final Research Achievements

To construct a structure-activity relationship, twenty-two derivatives of highly in vivo anticancer-active tetrazolato-bridged dinuclear platinum(II) complex were synthesized with variable substituents at tetrazolate C5. Most derivatives were found to be highly in vitro cytotoxic and to circumvent cross-resistance to cisplatin, which is the representative of platinum-based drugs. In addition, the cytotoxicity fingerprints of some derivatives based on the JFCR39 cytotoxicity data were completely different from those of clinical platinum-based anticancer drugs, as well as other anticancer agents. The terazolato-bridged complexes efficiently induce B to C DNA transformation of calf-thymus DNA and compaction of T4 phage DNA. The second- and higher-order structural changes cannot be observed in case of platinum-based drugs. Therefore, tetrazolato-bridged complexes are likely to exhibit cytotoxicity with a novel mechanism of action probably due to the unique interactions with DNA.

Free Research Field

生物無機化学