期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 7, 页码 3395-3406出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01860
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资金
- University del Piemonte Orientale
The synthesis, characterization, and in vitro activity of a cyclohexane-1R,2R-diamine-based Pt(IV) derivative containing the histone deacetylase inhibitor rac-2-(2-propynyl)octanoato, namely, (OC-6-44)-acetatodichlorido (cyclohexane-1R,2R-diamine)(rac-2-(2-propynyl)octanoato)platinum(IV), are reported together with those of its isomers containing enantiomerically enriched axial ligands. These Pt(IV) complexes showed comparable activity, of 2 orders of magnitude higher than reference drug oxaliplatin on three human (HCT 116, SW480, and HT-29) and one mouse (CT26) colon cancer cell lines. In vivo experiments were carried out on immunocompetent BALB/c mice bearing the same syngeneic tumor. The complex (OC-6-44)-acetatodichlorido(cyclohexane-1R,2R-diamine)(rac-2-(2-propynyl)octanoato)platinum(IV) showed higher tumor mass Pt accumulation than oxaliplatin, due to its higher lipophilicity, with negligible nephro- and hepatotoxicities when administered intravenously. A remarkable tumor mass invasion by cytotoxic CD8(+) T lymphocytes, following the Pt(IV) treatment, indicated a strong induction of immunogenic cell death.
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