Novel Therapeutic Agents for Bone Resorption. Part 1. Synthesis and Protonation Thermodynamics of Poly(amidoamine)s Containing Bis-phosphonate Residues

Two poly(amido-amine)s (oligoPAM and oligoNER) contg. bis-phosphonate residues were obtained by a Michael-type polyaddn. of pamidronate and neridronate to 1,4-bis(acryloyl)piperazine. The SEC (size-exclusion chromatog.) and the MALDI-TOF (matrix assisted laser desorption ionization) analyses were consistent with the presence of oligomeric species (2-3 kDa) and with a narrow polydispersity index. The thermodn. results (log Ks, -? H° , and ? S° obtained at 25°C in 0.15 M NaCl) of both the oligomers and the corresponding low mol. wt. precursors were in line with a cluster structure formed during the protonation of the basic nitrogen in the pamidronate. The soly. of the oligoNER with a longer aliph. chain was improved at high pHs, allowing the evaluation of their soln. properties. Preliminary biol. results show that both the oligomers do not neg. affect the in vitro viability, proliferation, and cellular activity of either normal animal or human osteoblasts.