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Novel therapeutic agents for bone resorption. Part 1. Synthesis and protonation thermodynamics of poly(amido-amine)s containing bis-phosphonate residues.

Casolaro M, Casolaro I, Spreafico A, Capperucci C, Frediani B, Marcolongo R, Margiotta N, Ostuni R, Mendichi R, Samperi F, Ishii T, Ito Y

Dipartimento di Scienze e Tecnologie Chimiche e dei Biosistemi, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy. casolaro@unisi.it

Two poly(amido-amine)s (oligoPAM and oligoNER) containing bis-phosphonate residues were obtained by a Michael-type polyaddition of pamidronate and neridronate to 1,4-bis(acryloyl)piperazine. The SEC (size-exclusion chromatography) 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 thermodynamic results (log Ks, -DeltaH(o) , and DeltaS(o) obtained at 25 degrees C in 0.15 M NaCl) of both the oligomers and the corresponding low molecular weight precursors were in line with a cluster structure formed during the protonation of the basic nitrogen in the pamidronate. The solubility of the oligoNER with a longer aliphatic chain was improved at high pHs, allowing the evaluation of their solution properties. Preliminary biological results show that both the oligomers do not negatively affect the in vitro viability, proliferation, and cellular activity of either normal animal or human osteoblasts.

Published 12 December 2006 in Biomacromolecules, 7(12): 3417-27.
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