A new series of bisphosphonates bearing either the nitrogen-containing NO-donor furoxan (1,2,5-oxadiazole 2-oxide) system or the related furazan (1,2,5-oxadiazole) in lateral chain has been developed. pKa values and affinity for hydroxyapatite were determined for all the compounds. The products were able to inhibit osteoclastogenesis on RAW 246.7 cells at 10 microM concentration. The most active compounds were further assayed on human PBMC cells and on rat microsomes. Unlike most nitrogen-containing bisphosphonates which target farnesyl pyrophosphate synthase, experimental and theoretical investigations suggest that the activity of our derivatives may be related to different mechanisms. The furoxan derivatives were also tested for their ability to relax rat aorta strips in view of their potential NO-dependent vasodilator properties.

Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs)

LOLLI, Marco Lucio;ROLANDO, Barbara;TOSCO, Paolo;DI STILO, Antonella;LAZZARATO, Loretta;OLIARO BOSSO, Simonetta;FRUTTERO, Roberta;GASCO, Alberto
2010

Abstract

A new series of bisphosphonates bearing either the nitrogen-containing NO-donor furoxan (1,2,5-oxadiazole 2-oxide) system or the related furazan (1,2,5-oxadiazole) in lateral chain has been developed. pKa values and affinity for hydroxyapatite were determined for all the compounds. The products were able to inhibit osteoclastogenesis on RAW 246.7 cells at 10 microM concentration. The most active compounds were further assayed on human PBMC cells and on rat microsomes. Unlike most nitrogen-containing bisphosphonates which target farnesyl pyrophosphate synthase, experimental and theoretical investigations suggest that the activity of our derivatives may be related to different mechanisms. The furoxan derivatives were also tested for their ability to relax rat aorta strips in view of their potential NO-dependent vasodilator properties.
BIOORGANIC & MEDICINAL CHEMISTRY
18
2428
2438
http://scienceserver.cilea.it/cgi-bin/sciserv.pl?collection=journals&journal=09680896
Bisphosphonates; nitric oxide; osteoclastogenesis; cardiovascular diseases
Marco L. Lolli; Barbara Rolando; Paolo Tosco; Shilpi Chaurasia; Antonella Di Stilo; Loretta Lazzarato; Eva Gorassini; Riccardo Ferracini; Simonetta Oliaro-Bosso; Roberta Fruttero; Alberto Gasco
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/71632
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