Dinuclear Platinum(II) Complexes with Bone‐Targeting Groups as Potential Anti‐Osteosarcoma Agents. Issue 13 (19th June 2017)

• Record Type: Journal Article
• Authors: Zhang, Zhenqin; Wang, Xiaoyong; Luo, Cheng; Zhu, Chengcheng; Wang, Kun; Zhang, Changli; Guo, Zijian
• Is Part Of: Chemistry, an Asian journal. Volume 12:Issue 13(2017)
• Page Start: 1659
• Page End: 1667
• Publication Date: 2017-06-19
• Subjects: anticancer drugs -- bisphosphonate derivatives -- bone-targeting agents -- osteosarcoma -- polynuclear platinum complexes; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/asia.201700577
• Languages: English
• ISSNs: 1861-4728

Abstract

Abstract: Osteosarcoma is the most common malignant bone tumor primarily affecting adolescents. Targeted platinum(II) complexes are promising candidates for overcoming the general toxicity of conventional platinum anticancer drugs. In this study four dinuclear platinum(II) complexes, {[ cis ‐Pt(NH3 )2 Cl]2 (PD)} (NO3 )2 (1 ), {[ cis ‐Pt(NH3 )2 Cl]2 (PDBP)} (NO3 )2 (2 ), {[ cis ‐Pt(DACH)Cl]2 (PD)} (NO3 )2 (3 ), and {[ cis ‐Pt(DACH)Cl]2 (PDBP)} (NO3 )2 (4 ) [PD=5, 5′‐carbonylbis(2‐(2‐(pyridin‐2‐yl)ethyl)isoindoline‐1, 3‐dione), PDBP=tetraethyl (((bis(1, 3‐dioxo‐2‐(2‐(pyridin‐2‐yl)ethyl)isoindolin‐5‐yl)methylene)amino) methylene)bis(phosphonate), DACH=1, 2‐diaminocyclohexane)], were designed and synthesized. The complexes were fully characterized by 1 H, 13 C, 195 Pt or 31 P NMR spectroscopy and HR‐MS. ICP‐MS studies showed that considerable amounts of Pt accumulate in U2OS osteosarcoma cells. The interactions of the complexes with calf thymus DNA and plasmid pUC19 DNA were investigated using CD and gel electrophoresis, which indicated that the complexes can react with DNA. The in vitro cytotoxicity showed that2 is the most potent complex towards U2OS cells. The cellular inhibition mode was examined by flow cytometry. Complex 2 kills U2OS cells predominately through an apoptotic pathway and arrests the cell cycle mainly in the G2 or M phase. The results demonstrate that dinuclear platinum(II) complexes with bone‐targeting groups could be anticancer agents for osteosarcoma. Abstract : On target : Bisphosphonate (BP)‐tethered dinuclear platinum complexes show significant inhibition against osteosarcoma cells. BP not only endows the platinum complexes with bone‐targeting property but also increases the lipophilicity and cellular uptake. Furthermore, the acute toxicity of the complexes is reduced by the BP targeting groups.