Cancer-Specific, Intracellular, Reductive Activation of Anticancer PtIVProdrugs.
Because cellular uptake of anticancer PtIIand PtIVdrugs occurs by different mechanisms, the latter ones can exhibit substantial activity towards cells, which have either intrinsic or acquired resistance towards PtIIdrugs. However, this positive effect is diminished due to reductive activation of PtIVdrugs 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 PtIVprodrug containing two pro-reductants. This hybrid was uptaken by cells, the pro-reductants were activated in the cancer-specific microenvironment (high H2O2), and reduced PtIVby 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.
Friedrich-Alexander-Universität Erlangen-Nürnberg, Department Chemistry and Pharmacy, Organic Chemistry II, Henkestrasse 42, 91301, Erlangen, Germany.
Viktor
V
Reshetnikov
Friedrich-Alexander-Universität Erlangen-Nürnberg, Department Chemistry and Pharmacy, Organic Chemistry II, Henkestrasse 42, 91301, Erlangen, Germany.
Steffen
S
Daum
Friedrich-Alexander-Universität Erlangen-Nürnberg, Department Chemistry and Pharmacy, Organic Chemistry II, Henkestrasse 42, 91301, Erlangen, Germany.
Andriy
A
Mokhir
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D005296:Ferrous Compounds / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D000075163:Metallocenes / Q000737:chemistry; D010984:Platinum / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005296:Ferrous Compounds; D000075163:Metallocenes; D011355:Prodrugs; D010984:Platinum; D006861:Hydrogen Peroxide; C004998:ferrocene
aminoferrocenes; cancer; electron transfer; platinum(IV) prodrugs; reactive oxygen species