Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance

Chemical Science
Emanuele PetruzzellaDan Gibson

Abstract

A series of triple action Pt(iv) prodrugs was designed to test the hypothesis that multi-action compounds, where each bioactive moiety intervenes in several cellular processes, might be more effective than a single agent at killing cancer cells. In particular, "triple action" Pt(iv) derivatives of cisplatin, where the axial ligands are inhibitors of cyclooxygenase (COXi), histone deacetylase (HDACi) or pyruvate dehydrogenase kinase (PDKi) were developed. All compounds, ctc-[Pt(NH3)2(COXi)(PDKi)Cl2], ctc-[Pt(NH3)2(COXi)(HDACi)Cl2] and ctc-[Pt(NH3)2(HDACi)(PDKi)Cl2], where COXi = aspirin or ibuprofen, PDKi = dichloroacetate and HDACi = valproate or phenylbutyrate, were significantly more cytotoxic than cisplatin against all cell lines of an in-house panel of human cancer cells. They were particularly effective against thyroid and pancreatic cancer cells in monolayer cytotoxicity tests. Remarkably, in 3D spheroid cancer cell cultures, some triple action compounds showed an antitumor potency up to 50-fold higher than cisplatin against a KRAS mutated pancreatic cancer cell line (PSN-1 cells). Standard biochemical assays classically employed to explore structure activity relationships of platinum drugs, such as cellular uptake and bi...Continue Reading

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Citations

Nov 30, 2018·International Journal of Molecular Sciences·Diego MontagnerCristina Marzano
Jan 12, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·Zhigang WangGuangyu Zhu
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Jan 13, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Yuewen SunXiaoyong Wang
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Dec 25, 2021·Frontiers in Chemistry·Eoin MoynihanDiego Montagner
Jan 12, 2022·Dalton Transactions : an International Journal of Inorganic Chemistry·Mauro RaveraDomenico Osella

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