Novel Bis-platinum Complexes Endowed with an Improved Pharmacological Profile
| Autor: | Laura Gatti, Elisabetta Corna, Gianluca Pardi, Cecilia Allievi, Nicoli Paola, Franco Zunino, N. Carenini, Stefano Di Giovine, Jack W. Singer, Mario Grugni, Sergio De Munari, P Apostoli, Marco Natangelo, Gabriella Pezzoni, Paola Perego, Roberto Leone, Ulla Bastrup |
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| Rok vydání: | 2009 |
| Předmět: |
Organoplatinum Compounds
Stereochemistry Kinetics Mice Nude Pharmaceutical Science chemistry.chemical_element Antineoplastic Agents Apoptosis Plasma protein binding DNA Mismatch Repair Bis-platinum complexes antitumor efficacy plasma binding drug development DNA Adducts Mice chemistry.chemical_compound Drug Stability Pharmacokinetics In vivo Cell Line Tumor Drug Discovery medicine Animals Humans Cisplatin Cell Cycle Xenograft Model Antitumor Assays Oxaliplatin chemistry Drug Resistance Neoplasm Drug Design Biophysics Molecular Medicine Female Platinum DNA medicine.drug |
| Zdroj: | Molecular Pharmaceutics. 7:207-216 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/mp900211j |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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