New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity.

Abstract

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.

• Authors: Alessandra Barbanente, Rosa Maria Iacobazzi, Amalia Azzariti, James D Hoeschele, Nunzio Denora, Paride Papadia, Concetta Pacifico, Giovanni Natile, Nicola Margiotta
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 26 Issue 11 (Jun 04 2021) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 34200051 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Oxaliplatin
• Cisplatin

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• Female
• HCT116 Cells
• Humans
• Hydrogen-Ion Concentration
• Male
• Molecular Structure
• Organoplatinum Compounds (chemical synthesis, chemistry, pharmacology)
• Oxaliplatin (analogs & derivatives)
• PC-3 Cells