Synthesis and cytotoxicity of N,N′-dibisphosphonate ethylenediamine derivatives and platinum(II) complexes with high binding property to hydroxyapatite

Abstract

A series of N,N′-dibisphosphonate ethylenediamine derivatives (L1–L6) and their corresponding dichloroplatinum(II) complexes (1–6) have been prepared and characterized by elemental analysis, 1H NMR, 13C NMR, 31P NMR, and HRMS spectra. The in vitro antitumor of compounds L1–L6 and 1–6 was tested by WST-8 assay with Cell Counting Kit-8, indicating that platinum-based complexes 1–6 showed higher cytotoxic efficacy than platinum-free compounds L1–L6 against SKOV3 and MG-63, especially complex 2 (R=CH3, n=2) with comparable cytotoxicity to cisplatin after 72h incubation. And complexes 1–6 were highly selective in cytotoxicity against MG-63 tumor cells than hFOB 1.19 normal cells. The in vitro hydroxyapatite binding test revealed that complexes 1 and 2 showed higher affinity (K′=4.2 and 3.5, respectively) for bone hydroxyapatite than cisplatin (K′<0.1) and zoledronate (K′=2.8). On basis of flow cytometry results, complex 2 induced cell death by apoptosis effect similar to cisplatin, different from zoledronate. Representative complex 2 has been proved to be a promising bone-targeting antitumor agent for subsequent in vivo study.