Thanks to their structural similarity with pyrophosphate, gem-bisphosphonates (BPs) ensure specific bone targeting and are widely employed as drugs for the treatment of bone disorders like osteoporosis, Paget disease and cancer. New recent studies demonstrated the cellular activity of nitrogen containing BP (N-BP) bearing long alkyl chain acting as potent inhibitors of specific enzymes thus leading to inactivation of osteoclasts that are the cells deputed to bone resorption.1 Herein we present a straightforward synthesis of a new class of β-substituted alkylidene bisphosphates precursors on wich Cu(II) mediated conjugate addition of indoles gave new N-BPs bearing different indolyl derivatives. A modified Knoevenagel condensation of oxalates and aril -ketoesters with methylen-bisphosphate (MBP) was carried out in the presence of TiCl4. The present system provided a facile access to a new class of mono and bi-substituted BP precursors in high yields endowed with an ester moiety. While Cu(II)-catalyzed addition of indoles to the new bis-substituted BP precursors could not be performed, addition to the mono ester substituted BP proceeded readily providing the desired compounds in good yields. It is worth noting that the same reaction on aryl substituted prochiral BPs could not be possible and this further underlines the importance of the newly discovered class of prochiral BPs. The effect of the length of the alkyl chain in the ester moiety was investigated as well. This efficient and versatile synthesis of BPs allowed the preparation of several BP tetraethyl esters that were deprotected removing the ester moieties forming the corresponding bisphosphonic acids2 that are currently under investigation to assess their activity in the inhibition of the osteoclast activity.
|Titolo:||Facile Cu(II) Mediated Addition of Indoles to a New Class of Bisphosphonate Precursors|
|Data di pubblicazione:||2016|
|Appare nelle tipologie:||4.3 Poster in Atti di convegno|
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|abstract CDCO2016.pdf||Abstract||Documento in Post-print||Accesso chiuso-personale||Riservato|