Bisphosphonates biological activities

Bisacylphosphonates (50) and bishydroxyiminophosphonates (51) were found to be the first examples of non-geminal bisphosphonates biologically active in calcium metabolism disorders such as pathological calcification and bone resorption These compounds showed less toxic side-effects and improved bioavailability than bisphosphonates approved for clinical use. ... 

Contrary to the original assumption which linked the inhibition of bone resorption solely to physico-chemical adsorption of the BP onto the bone surface, there is new evidence indicating cellular mechanisms of BP action, although a prerequisite of the biological activity is still the adsorption. The bisphosphonates deposited on the bone surface poison the bone-resorbing osteoclasts after being internalized by them. 

Ebetino FH, Hogan AL, Sun S, Tsoumpra MK, Duan X, Triffitt JT, Kwaasi AA, Dunford JE, Barnett BL, Oppermann U et al (2011) The relationship between the chemistry and biological activity of the bisphosphonates. Bone 49 20-33... 

In 1999, Komagata et al. described the synthesis of bisphosphonic acids and esters linked through an alkyl spacer to ort/to-carborane (39-41) in a patent application. These boron-containing phosphonates were proposed for use as BNCT agents in the treatment of bone tumors. However, no data concerning the biological activity of these compounds were given. 

Due to the biological activity of bisphosphonic acids, a vast array of derivatives and precursors have been generated including bile salts (Scheme 4.166) [255]. The overall process started with protection of the alcohols on the parent bile salt through the addition of formic add. Once suitably protected, the addition of thionyl chloride converted the carboxylic acid into an add chloride. Since these conversions are typically carried out using an excess of the thionyl chloride, the ranoval of unreacted material can be particularly troublesome. In these reactions, the ranoval of the excess thionyl chloride was achieved through repeated trituration with benzene. The final steps in the synthesis entailed... 

The benzothiophene derivative raloxifene (Evista /Lilly) is a selective estrogen receptor modulator (SERM). Raloxifene produces its biological actions via modulation (both activation and blockade) of estrogen receptors that ultimately results in decreased resorption of bone. The bisphosphonate derivative alendronate (Fosamax /Merck), an inhibitor of osteoclast-mediated bone resorption, is also useful in the treatment of osteoporosis. Both raloxifene and alendronate are useful in the treatment of osteoporosis in postmenopausal women. 

Macrocyclic bisphosphonates 165 and 166 were evaluated in vitro for calcium-ion-releasing activity from sea urchin egg homogenates. Both cADPR[CH2] 165 and 3-deaza-cADPR[CH2] 166 induced Ca release but, in comparison to the natural substrate (cADPR), they were 15- and 5-fold less potent, respectively. Also, 3-deaza-cADPR[CH2] 166 was found to be 375-fold less efficient than 3-deaza-cADPR in this study. The pyrophosphate moiety plays a cmcial role in the biological response and probably contributes to ligand—receptor interactions (05JMC4177). 

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