New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity

Molecules

Paride Papadia¹  James D. Hoeschele²  Giovanni Natile³  Nicola Margiotta³  Alessandra Barbanente³  Concetta Pacifico³  Nunzio Denora⁴  Rosa Maria Iacobazzi⁵  Amalia Azzariti⁵ 

[1] Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Prov.le Lecce-Monteroni, Centro Ecotekne, 73100 Lecce, Italy;Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197, USA;Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy;Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy;Laboratorio di Farmacologia Sperimentale, IRCCS Istituto Tumori “Giovanni Paolo II”, O. Flacco St., 70124 Bari, Italy;

关键词: cisplatin;    oxaliplatin;    phosphaplatins;    pyrophosphate;    bone tumors;    antitumor drugs;   

DOI  :  10.3390/molecules26113417

来源: DOAJ

【 摘 要 】

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na₂[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5’-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5’-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells’ death by apoptosis and necrosis.

【 授权许可】

Unknown