Bisphosphonate analogs

Bisphosphonic acids and their salts are analogs of pyrophosphate where the P-O-P linkage of the latter has been replaced by P-C-P. Bisphosphonates are known to inhibit bone resorption, and have attracted much attention as potential therapeutic agents. Bisphosphonates do not absorb or fluoresce, and sample matrix interferences can make detection difficult, especially in biological samples. Successful applications of IEC to bisphosphonate analysis have been described.173174... 

Table XIX contains stability constants for complexes of Ca2+ and of several other M2+ ions with a selection of phosphonate and nucleotide ligands (681,687-695). There is considerably more published information, especially on ATP (and, to a lesser extent, ADP and AMP) complexes at various pHs, ionic strengths, and temperatures (229,696,697), and on phosphonates (688) and bisphosphonates (688,698). The metal-ion binding properties of cytidine have been considered in detail in relation to stability constant determinations for its Ca2+ complex and complexes of seven other M2+ cations (232), and for ternary M21 -cytidine-amino acid and -oxalate complexes (699). Stability constant data for Ca2+ complexes of the nucleosides cytidine and uridine, the nucleoside bases adenine, cytosine, uracil, and thymine, and the 5 -monophosphates of adenosine, cytidine, thymidine, and uridine, have been listed along with values for analogous complexes of a wide range of other metal ions (700). Unfortunately comparisons are sometimes precluded by significant differences in experimental conditions.

The bisphosphonates are analogs of pyrophosphate in which the P-O-P bond has been replaced with a nonhydrolyzable P-C-P bond (Figure 42-4). Etidronate, pamidronate, and alendronate have now been joined by risedronate, tiludronate, ibandronate, and zoledronate for clinical use. The bisphosphonates owe at least part of their clinical usefulness and toxicity to their ability to retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. They localize to regions of bone resorption and so exert their greatest effects on osteoclasts. However, the exact mechanism by which they selectively inhibit bone resorption is not clear. 

Analogous reaction sequences performed in the presence of excess base and phosphonylating reagent diethyl phosphorochloridate provided a series of new a,a-bisphosphonates (309) (Scheme 80). ... 

By analogy with bisphosphonates, bisphosphinic acids were recently synthesized for their complexing abilities (Scheme 63) [228]. The synthesis was... 

Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor used to treat hypercalcemia associated with malignancy and osteolytic bone lesions associated with multiple myeloma, metastatic breast cancer, and moderate to severe Paget s disease of bone. Aredia, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as phosphonic acid (3-amino-l-hydroxypropylidene) bis-, disodium salt, pentahydrate, (APD). 

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