1,2,3-Triazole Fluorescent Bisphosphonates as Osteoporosis Probes Drugs

Thanks to their structural similarity with pyrophosphate, bisphosphonates (BPs) ensure specific bone targeting and are widely employed as drugs for the treatment of bone disorders, in particular osteoporosis whose costs, every year, were estimated in €37 billion treating approximately 27.5 million affected people in Europe.[1] Recent studies have demonstrated that zoledronic acid, one of the most potent drugs under use, characterized by the presence of a 1,3-diazole bisphosphonate strucutre, is among the most efficient inhibitor of specific enzymes [2] leading to osteoclast inactivation and apoptosis. In the present contribution we present the syntheses of  and azido-BP “Click reaction reagents” in order to obtain a new potentially highly efficient class of 1,2,3-triazole BPs. The synthesis of the -azido BP proceeded readily via Pd(II)-catalyzed addition of azidotrimethylsilane [3] to vinylidenebisphosphonate tetraethylesters (VBP), providing a quantitative yield of the desired compound, using an improved procedure. -Azido BP can be obtained by Cu(II)-assisted diazo-transfer reaction to a amino-BP using imidazole-1-sulfonyl azide hydrochloride as a safe diazo-transfer reagent compared to the commonly employed triflyl azide.[4] These efficient syntheses allowed the preparation of the azido-BPs in multigram scale that were tested in click chemistry reactions (Cu(I)-catalyzed azide-alkyne cycloadditions), giving 1,4-di-substituted 1,2,3-triazoles BP products with high regioselectivity. Reaction with several terminal alkynes, including a triple-bond functionalized diketopyrrolopyrrole (DPP) fluorescent dye, gave a new class fluorescent BP probes for bone imaging.