title: Cytotoxicity-boosting of kiteplatin by Pt(IV) prodrugs with axial benzoate ligands.
abstract: Kiteplatin, the neglected drug analogous of cisplatin but containing cis-1,4-DACH in place of the two ammines, has been recently reevaluated for its activity against cisplatin- and oxaliplatin-resistant tumors, in particular colo-rectal cancer. With the aim of further improving the pharmacological activity of this drug, Pt(IV) prodrugs were derived by addition of two, differently substituted, benzoate groups in axial positions (X-ray structure). The cytotoxic activity of both compounds resulted markedly potentiated reaching nanomolar concentration against a wide panel of human cancer cells. The ability of benzoate ligands to enhance the activity of kiteplatin most likely originates from their lipophilicity promoting a higher drug accumulation in cancer cells; however, it is to be noted that the increase in pharmacological effect is far greater than the increase in cellular uptake. Overcoming cisplatin- and oxaliplatin-resistance by kiteplatin derivatives appears to relate to the inability of membrane extrusion pumps to remove active Pt species from tumor cells.
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy. Electronic address: nicola.margiotta@uniba.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: Margiotta
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Savino
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Pacifico
authors.affiliation: Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Hoeschele
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy. Electronic address: giovanni.natile@uniba.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry*; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000077150:Oxaliplatin; D010984:Platinum / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D008024:Ligands; D009944:Organoplatinum Compounds; D011355:Prodrugs; C445102:platinum(II)(1,4-diazacycloheptane)dichloride; D000077150:Oxaliplatin; D010984:Platinum; D002945:Cisplatin
keywords: Benzoate ligands; Cell growth inhibition; Cellular accumulation; Kiteplatin; Pt(IV) complexes; X-ray crystal structure