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The biological effects of bisphosphonates in calcium-related disorders are attributed to the incorporation of the bisphosphonates in bone, enabling direct interaction with osteoclasts and/or osteoblasts. The high accumulation of bisphosphonates in bone, due to their high affinity to hydroxyapatite (HAP), is essential for mediating in vitro and in vivo activity. In this study we examined the activity of tetrakisphosphonates, molecules containing two P-C-P type bisphosphonate moieties connected by a carbon chain. The novel compounds were examined in a battery of in vitro and in vivo models including HAP formation and dissolution, ectopic calcification, bone resorption, tumor osteolysis, and of macrophage-like cells (anti- or pro-inflammatory properties). The inhibition of ectopic calcification was ranked as follows: geminal bisphosphonates > bisacylphosphonates > tetrakisphosphonates. Pamidronate, but not the tetrakisphosphonates, was an effective antiosteolytic agent. Neither DNTP (tetrasodium 1,9-dihydroxynonane 1,1,9,9-tetrakisphosphonate) nor the bisacylphosphonate, PiBP (pimeloylbisphosphonate) seem to possess strong macrophage suppressive or inductive effects and can be considered to be relatively inactive in terms of anti- or pro-inflammatory action. A significant anticalcification effect was caused by various phosphonates, such as the tetrakisphosphonates, but DNTP, a tetrakisphosphonate, was found toxic as it impeded somatic growth and bone development.

The intraannular introduction of a halogen into a calixarene skeleton is described. Monoaminotetrahydroxy-p-tert-butylcalix[5]arene (2b) was diazotized by treatment with isoamyl nitrite/HCl/EtOH. Thermal dediazoniation of the salt in chloroform yielded monochlorotetrahydroxy-p-tert-butylcalix[5]arene (5a) and the xanthenocalix[5]arene 6. These products result from the capture of an intermediate phenyl cation derivative by chloride ion or intramolecularly, by a neighboring phenol ring. The product ratio 6:5a was not affected by the addition of excess external chloride, suggesting that the reacting intermediate exists as an ion pair. The dediazoniation reaction in the presence of bromide and iodide ions afforded the corresponding halocalixarenes 5b and 5c, while in the presence of a fluoride ion the calixindazole 8 was obtained. X-ray diffraction indicates that 5b exists in a distorted cone conformation (cone-in) in which the extraannular edge of the halophenyl ring is tilted toward the cavity center. The halocalixarenes undergo a cone-to-cone inversion process with a barrier in the 11.3−12.5 kcal mol-1 range in CDCl3. The barrier height is a function of the size of the halo substituent. Xanthenocalix[5]arene 6 crystallizes with three ethanol solvent molecules and exists in a cone-like conformation.

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