Cancer‐Specific, Intracellular, Reductive Activation of Anticancer Pt^IV Prodrugs

Abstract

Because cellular uptake of anticancer Pt and Pt drugs occurs by different mechanisms, the latter ones can exhibit substantial activity towards cells, which have either intrinsic or acquired resistance towards Pt drugs. However, this positive effect is diminished due to reductive activation of Pt 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 prodrug containing two pro-reductants. This hybrid was uptaken by cells, the pro-reductants were activated in the cancer-specific microenvironment (high H O ), and reduced Pt 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.

N-Alkylaminoferrocene-Based Prodrugs Targeting Mitochondria of Cancer Cells

“…We conjugated a representative NAAF prodrug 4 to two known mitochondria-carriers (alkyltriphenylphosphonium (Ph 3 P-R + ) [20] and N,N,N ,N -tetramethylrhodamine (TMR + )) by using Cu + -catalyzed azide-alkyne cycloaddition ("click" reaction) leading to prodrugs 5 and 7 (Scheme 2). Additionally, control compounds (lysosome-targeting prodrug 8 [18], non-targeted prodrugs 9 [21] and 10 [7,8] as well as "empty" carriers 12 [22] and 13) were prepared as described in the supporting information (SI). Our carrier selection was based on the following considerations.…”

ROS‐Responsive N‐Alkylaminoferrocenes for Cancer‐Cell‐Specific Targeting of Mitochondria

“…It is based on an N‐alkylaminoferrocene (NAAF) moiety protected with a ROS sensitive group=N‐carbonyloxymethylphenylboronic acid pinacol ester (compounds 1 – 3 ; Figure B). The ROS‐dependent activation of related structures (such as 4 – 6 ) has been previously explored by our group to design anticancer prodrugs acting via ROS amplification, lysosomal disruption, and DNA‐modification –. Application of other ferrocene derivatives as anticancer drugs has been extensively reviewed …”

“…This work: a concept of pro‐DLCs activated in the presence of cancer specific amounts of ROS with formation of DLCs. B) Structures of pro‐DLCs 1 – 3 , their activated derivatives DLCs 1_I – 3_I , and previously reported reference compounds 4 – 6 –. C) Structures of control compounds.…”

“…Cancer‐cell targeting by the pro‐DLCs is defined by two factors: factor I is formation of DLCs in the presence of cancer specific, elevated amounts of ROS;– and factor II is accumulation of the DLCs formed (NAAF + ) preferably in mitochondria of cancer cells, owing to their higher transmembrane potential (ΔΨ c ). The cancer cell specificity of these pro‐DLCs was expected to be higher than that of known single‐mode systems (Figure ).…”

Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

“…20,21 This prodrug strategy has been widely used for the construction of multifunctional Pt complexes as illustrated in many studies. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] BRCA and RAD51 play essential roles in HR, and BRCA-procient tumors are usually refractory to CDDP due to effective HR. Recently, we designed two Pt IV -artesunate prodrugs, which inhibited HR via downregulating RAD51 and exhibited higher cytotoxicity against BRCA-procient cancer cells than CDDP.…”