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

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, H-1 NMR, C-13 NMR, P-31 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 72 h 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. (C) 2016 Elsevier B.V. All rights reserved.