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An unsymmetric cisplatin-based Pt(IV) derivative containing 2-(2-propynyl)octanoate: a very efficient multi-action antitumor prodrug candidate

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Abstract

The design, synthesis, characterization and biological properties of a Pt(IV) complex containing the very active inhibitor of histone deacetylase (2-propynyl)octanoic acid, POA, as an axial ligand are reported here. The title complex, namely (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(IV), 1, containing POA in racemic or in enantiomeric forms, was one/two orders of magnitude more active than cisplatin, depending on the chemo-sensitivity of the cancer cell lines. Moreover, 1 exhibited similar or even better antiproliferative activity than (OC-6-33)-diamminedichloridobis(2-propylpentanoato)platinum(IV), 2, containing two molecules of the well-known histone deacetylase inhibitor 2-propylpentanoic (valproic) acid. The high potency of 1 is likely due to its high cellular accumulation and to the synergism between the DNA-damaging cisplatin and the histone deacetylase inhibitor POA, both released upon the intracellular reduction of 1. Prodrug 1, after oral administration, caused an impressive reduction of the tumor mass (94%) in a model of solid tumor (murine Lewis lung carcinoma), compared to that of the control, whereas (intraperitoneal) cisplatin induced a tumor regression of 75% only. A good accumulation of 1 was observed in the tumor mass. The time course of the body weight attested that cisplatin induced elevated anorexia, whereas treatment with 1 did not induce significant body weight loss throughout the therapeutic experiment.

Graphical abstract: An unsymmetric cisplatin-based Pt(iv) derivative containing 2-(2-propynyl)octanoate: a very efficient multi-action antitumor prodrug candidate

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Publication details

The article was received on 08 Aug 2017, accepted on 22 Sep 2017 and first published on 22 Sep 2017


Article type: Paper
DOI: 10.1039/C7DT02928D
Citation: Dalton Trans., 2017, Advance Article
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    An unsymmetric cisplatin-based Pt(IV) derivative containing 2-(2-propynyl)octanoate: a very efficient multi-action antitumor prodrug candidate

    E. Gabano, M. Ravera, I. Zanellato, S. Tinello, A. Gallina, B. Rangone, V. Gandin, C. Marzano, M. G. Bottone and D. Osella, Dalton Trans., 2017, Advance Article , DOI: 10.1039/C7DT02928D

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