TY - JOUR
T1 - Pt(IV) Bifunctional Prodrug Containing 2-(2-Propynyl)octanoato Axial Ligand
T2 - Induction of Immunogenic Cell Death on Colon Cancer a
AU - Sabbatini, Maurizio
AU - Zanellato, Ilaria
AU - Ravera, Mauro
AU - Gabano, Elisabetta
AU - Perin, Elena
AU - Rangone, Beatrice
AU - Osella, Domenico
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/4/11
Y1 - 2019/4/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85063569557&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b01860
DO - 10.1021/acs.jmedchem.8b01860
M3 - Article
SN - 0022-2623
VL - 62
SP - 3395
EP - 3406
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -