Novel bis-platinum complexes endowed with an improved pharmacological profile

Molecular Pharmaceutics
Laura GattiFranco Zunino

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 (bis-capronate) 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 r...Continue Reading

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Citations

Mar 9, 2011·Dalton Transactions : an International Journal of Inorganic Chemistry·Rasha A RuhayelNicholas P Farrell
May 18, 2010·International Journal of Cancer. Journal International Du Cancer·Ho-Shin GwakOliver Bögler
Nov 22, 2013·Molecular Pharmaceutics·Laura GattiPaola Perego
Jan 29, 2016·Dalton Transactions : an International Journal of Inorganic Chemistry·Claire S Allardyce, Paul J Dyson
May 6, 2010·Dalton Transactions : an International Journal of Inorganic Chemistry·Nicolas P E BarryBruno Therrien
Nov 1, 2020·Nature Reviews. Cancer·Sven RottenbergPaola Perego

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