Novel bis-platinum complexes endowed with an improved pharmacological profile

Laura Gatti, Paola Perego, Roberto Leone, Piero Apostoli, Nives Carenini, Elisabetta Corna, Cecilia Allievi, Ulla Bastrup, Sergio De Munari, Stefano Di Giovine, Paola Nicoli, Mario Grugni, Marco Natangelo, Gianluca Pardi, Gabriella Pezzoni, Jack W. Singer, Franco Zunino

Research output: Contribution to journalArticlepeer-review

Abstract

Multinuclear platinum complexes are characterized by a peculiar DNA binding mode and higher cytotoxic potency than the mononuclear complexes, and efficacy against a wide range of preclinical tumor models. To reduce the high irreversible plasma protein binding and improve the chemical and metabolic drug stability, novel bis-platinum complexes were designed starting from the parent compound CT-3610. The novel second-generation bis-platinum complexes utilize alkylcarboxylate as leaving groups to improve their pharmacokinetic and pharmacodynamic profiles, thus overcoming the limitations of the previously developed multinuclear compounds. The selected compounds [CT-47518 and CT-47463, respectively (biscapronate) platinum and (bis-butyrate) platinum], have similar in vitro degradation kinetics in human and murine plasma and, above all, an increased stability when compared to CT-3610, particularly in human plasma. In addition, both compounds exhibited a marked cytotoxic potency as compared with cisplatin and oxaliplatin. Interestingly, they were capable of overcoming resistance mediated by DNA mismatch repair defects in different cellular models. The complexes showed marked antitumor efficacy in Pt-refractory tumor xenografts, with remarkable activity in terms of tumor growth inhibition and tumor growth delay. The improved stability profile in human plasma compared to early bis- and triplatinum complexes together with the marked activity in cellular systems as well as in in vivo models, make CT-47518 and CT-47463 attractive candidates for further development.

Original languageEnglish
Pages (from-to)207-216
Number of pages10
JournalMolecular Pharmaceutics
Volume7
Issue number1
DOIs
Publication statusPublished - Feb 1 2010

Keywords

  • Antitumor efficacy
  • Bis-platinum complexes
  • Drug development
  • Plasma binding

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

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