Bone targeted new zoledronate derivative: design, synthesis, ^99mTc-coupling, in-silico study and preclinical...

Background: Zoledronate suppresses human sarcomas by blocking the formation of geranylgeranyl diphosphate (GGPP) via inhibiting GGPP synthase.Objectives: Designing of new derivative of dronic acid (1-hydroxy-2-(4-nitro-1H-imidazol-1-yl)ethan-1,1-diyl)bis phosphonic acid), structurally related to zoledronate to be used for osteosarcoma therapy.Methods: 1-hydroxy-2-(4-nitro-1H-imidazol-1-yl)ethan-1,1-diyl)bis(phosphonic acid) was synthesized in one pot reaction with a yield of 65 ± 4%. The synthesized nitro-zoledronate compound was successfully radiolabeled with ^99mTc with a radiochemical purity of 92.05%. Docking accuracy and scoring reliability for the new nitro-zoledronate with human GGPPS using MOE software has been presented.Results and Conclusion: The nitro-zoledronate successfully coupled with technetium-99m at high yield to investigate its in-vivo biodistribution which indicated highly selective uptake in the skeletal system and rapid clearance from soft tissues. The in-vitro cytotoxicity of the nitro-zoledronate was evaluated and potently inhibited the osteosarcoma cell line (MG-63) after 72 hours with an IC50 value of 10 μM. To summarize, our data point to a promising candidate to improve osteosarcoma therapy.