Premium
Cancer‐Specific, Intracellular, Reductive Activation of Anticancer Pt IV Prodrugs
Author(s) -
Reshetnikov Viktor,
Daum Steffen,
Mokhir Andriy
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201701192
Subject(s) - prodrug , intracellular , extracellular , chemistry , drug , cisplatin , cancer cell , cell culture , pharmacology , cancer research , combinatorial chemistry , cancer , biochemistry , chemotherapy , medicine , biology , genetics
Because cellular uptake of anticancer Pt II and Pt IV drugs occurs by different mechanisms, the latter ones can exhibit substantial activity towards cells, which have either intrinsic or acquired resistance towards Pt II drugs. However, this positive effect is diminished due to reductive activation of Pt IV drugs in extracellular space that can be one of the reasons why they have not yet been approved for clinical use despite over 60 clinical trials conducted worldwide. Herein, we suggest a solution to this problem by achieving highly specific intracellular versus extracellular prodrug reduction. In particular, we prepared a hybrid Pt IV prodrug containing two pro‐reductants. This hybrid was uptaken by cells, the pro‐reductants were activated in the cancer‐specific microenvironment (high H 2 O 2 ), and reduced Pt IV by two one‐electron transfers. The drug formed in this way induced cell death both in cisplatin‐sensitive and resistant cell lines, but remained nontoxic to normal cells.