Pt(IV) Anticancer Prodrugs – A Tale of Mice and Men

Abstract

We would like to be able to design Pt(IV) prodrugs that can overcome resistance and minimize side effects. Unlike with the early exploration of Pt(II) anticancer agents where clear structure‐activity relationships were defined, even after more than two decades of research on Pt(IV) prodrugs, there is no roadmap that can point us to the holy grail. Despite many excellent rational endeavors, we still have not found the “right” two axial ligands to append to the Pt(IV) derivatives of platinum(II) drugs that will “make platinum great again”. So far this proved elusive, indicating that the design of Pt(IV) prodrugs is a difficult and frustrating task. Despite our better understanding of the biological processes and availability of advanced technologies, even our sophisticated rational plans often leave us disappointed and frustrated because at the end of the day, we are not able to outsmart the cancer cells or the mice, and just like Rosenberg, we might need to be rescued by serendipity.

Multifunctional platinum(iv) complex bearing HDAC inhibitor and biotin moiety exhibits prominent cytotoxicity and tumor-targeting ability

“…[19][20][21] Thus, platinum(IV) anticancer agents with high kinetic inertness have become the research focus, and great improvements have been achieved in recent years. [22][23][24][25] For example, different bioactive and tumor-targeting groups have been introduced to platinum(IV) agents, on the one hand, to improve the selectively of platinum(IV) complexes, and on the other hand, have been used to overcome the drug resistance of platinum(II) drugs. [26][27][28][29][30][31][32][33][34][35][36] In addition, photoactivated platinum(IV) complexes have shown unique advantages in overcoming the limitations of the currently used platinum(II) drugs, [37][38][39][40] especially for red light-excited platinum(IV) agents with deeper tissue penetration.…”

Synthesis and characterization of thiocarbonato-linked platinum(iv) complexes

“…Besides cisplatin and carboplatin, oxaliplatin is one of the most well-known platinum(II) complexes with chemotherapeutical potential. [1][2][3][4][5][6][7][8] It is applied in the treatment of colorectal, pancreatic and gastric cancer, alone or in combination with other drugs. [9][10][11][12][13][14][15][16] As part of the third generation of platinum drugs, oxaliplatin is armed with the bidentate ligand R,R-DACH and the chelating oxalate ligand, both increase its kinetic stability.…”

“…17 After hydrolysis of the leaving group, the activated platinum(II) complex forms adducts with two adjacent guanines or guanine and adenine in DNA strands, thus interfering with DNA replication and transcription and inducing cell death. 1,2,9,14,17,18 Cancer treatment with platinum(II) complexes is accompanied by severe side-effects and mechanisms of intrinsic or acquired resistance. To overcome these drawbacks, researchers have traced the path of platinum(IV) complexes.…”

“…To overcome these drawbacks, researchers have traced the path of platinum(IV) complexes. 1,2,7,[17][18][19][20][21][22][23][24] Investigation into the anticancer potential of octahedral platinum(IV) prodrugs with two additional axial ligands is of current interest due to their lower toxicity and higher kinetic stability compared to platinum(II) complexes, and promising effects on cisplatin-resistant cells. Inside the cell, platinum(IV) complexes are reduced by intracellular biomolecules and release the cytotoxic platinum(II) complex and its free axial moieties.…”

Potential Anticancer Activities and Catalytic Oxidation Efficiency of Platinum(IV) Complex

“…Most reported Pt(IV) prodrugs are structurally-related to cisplatin (using the cis-PtCl 2 (NH 3 ) 2 with two extra axial ligands). Axial ligands can be biologically-inactive such as hydroxido or halo ligands [ 10 , 11 ] or biologically active ligands [ 12 , 13 , 14 , 15 , 16 ]. The compound cis, trans -[PtCl 2 (OOCCH 3 ) 2 (NH 3 )(NH 2 Cy)] (known as satraplatin) exhibits a promising toxicity profile against breast, prostate and lung cancer [ 17 ] and was progressed to phase III clinical trial against hormone-refractory prostate cancer (PC); however, there was no overall survival benefit.…”