Ada Schlossman

Bisacylphosphonates inhibit hydroxyapatite formation and dissolution in vitro and dystrophic calcification in vivo

Some geminal bisphosphonates are used clinically for a number of important bone/calcium related diseases; however, side effects and lack of selectivity impede their wide use. This work reports the synthesis and evaluation of bisacylphosphonates (e.g., adipoyl- and suberoylbisphosphonate). These compounds were found to inhibit significantly hydroxyapatite formation and dissolution in vitro and the calcification of bioprosthetic tissue implanted subdermally in rats. These are the first instances of nongeminal bisphosphonates [P–(C)n– P, n ≥ 2] that have been reported to be active in calcium-related disorders. The reported bisacylphosphonates possess apparent lower toxicity, and their calcium complexes/salts have improved solubility properties. Therefore, they are of potential importance for clinical applications.

Anticalcification and antiresorption effects of bisacylphosphonates

Some geminal bisphosphonates are used clinically in a number of important bone and calcium-related diseases. This work reports the anticalcification and antiresorption effects of a series of bisacylphosphonates, nongeminal compounds with varying chain lengths having oxo groups in alpha positions relative to the phosphonic functions. We compared the activity of the novel compounds to clinically used geminal bisphosphonates, and to a bisphosphonate devoid of the oxo groups. The interaction of the compounds with calcium was studied by various in vitro and in vivo models. We found that keto groups in alpha positions to the phosphonic functions render activity. The bisacylphosphonates with a shorter chain [(CH2)n, = 4, 6] were found significantly to inhibit hydroxyapatite formation and dissolution in vitro, the calcification of bioprosthetic tissue implanted subdermally in rats, and bone resorption in the intact young animal model. The various in vitro results were found to be in good correlation with the in vivo results. Structure-activity relationship studies indicate that both bisacylphosphonates and geminal bisphosphonates are active only when at least three ionizable groups are present in the molecule. The role of the keto groups is related to their contribution to chelating calcium and/or to their electron-withdrawing influence on acidity.

Long‐chain functional bisphosphonates: synthesis, anticalcification, and antiresorption activity

Bisacylphosphonates have previously been shown to possess in vitro activity with regard to hydroxyapatite (HAP) formation and dissolution, and in vivo on tissue calcification and bone resorption. This work was aimed at elucidating the role of the keto groups in the biological activity of these compounds. For this purpose, we have synthesized a series of long-chain bisphosphonates possessing different functional groups adjacent to the phosphonic functions and examined them in some in vitro and in vivo models. The functional groups introduced into the newly synthesized bisphosphonates (hydroxyl, amide, and difluoromethylene) were chosen as to represent certain isolated aspects of the keto groups in the original compounds. None of the functional groups introduced into the long chain bisphosphonates bestowed higher activity on the molecules than the carbonyl groups. The unique effect of the α-keto groups in rendering long-chain bisphosphonates active is presumably attained through a combination of chelating ability with sufficiently low pKa values to enable the bisacylphosphonate molecules to be fully ionized at physiological pH.

Stereoselectivity in fragmentation and rearrangement of α-hydroxyimino-phosphinates and -phosphonates. A synthetic approach to acylphosphon- and phosphor-amidates. Crystal structures of methyl (E)-α-hydroxyimino-benzylphenylphosphinate and methyl benzoylphenylphosphonamidate

Reaction of methyl benzoylphenylphosphinate 1 with hydroxylamine gave methyl α-hydroxy-iminobenzylphenylphosphinate 2 as a mixture of E and Z isomers with the E isomer predominating. Pure (E)-2 when heated gave methyl N-benzoylphenylphosphonamidate 3 as the sole product. In contrast, (Z)-2 when heated gave, as a result of fragmentation, mainly methyl hydrogen phenylphosphonate 4 and benzonitrile, together with methyl N-phenylcarbamoylphenylphosphinate 5 as the minor product; the latter results from Beckmann rearrangement of (Z)-2. Analogous behaviour is exhibited by the two geometrical isomers of dimethyl α-hydroxyiminobenzylphosphonate 8. The crystal structures of methyl (E)-α-hydroxyiminobenzylphenylphosphinate (E)-2 and methyl benzoylphenylphosphonamidate 3 are reported.

Novel Bisphosphonates for Calcium-Related Disorders

Bisphosphonates are drugs used clinically in various calcium-related disorders such as Pagets disease, hypercalcemia of malignancy, and tumor osteolysis and are undergoing clinical trials for osteoporosis. From the results obtained in various clinical studies using conventional bisphosphonates, it appears that there is a need for compounds with a greater margin between the inhibition of bone resorption and the inhibition of mineralization, without an accompanying increase in toxicity, and at the same time, improved oral bioavailability without gastrointestinal side effects. One research strategy to address these problems is the synthesis and evaluation of non-geminal bisphosphonates, bisacylphosphonates. It is concluded that a new generation of calcium-binding compounds with antiresorptive and anticalcification properties have been obtained. In comparison to clinically used bisphosphonates, the new compounds posses very low toxicity and improved bioavailability.

In vitro and in vivo inhibition of hydroxyapatite formation and dissolution by bisacylphosphonates and bishydroxyiminophosphonates

Abstract Certain irregularities in calcium metabolism such as Pagets disease, osteoporosis, as well as osteolysis in bone cancer, are characterized by excessive destruction of the bone by resorption. In contrast, a number of clinically important diseases, for example, atherosclerosis, kidney and renal calculu8, arthritis, and bioprosthetic heart valve calcification are characterized by the deposition of calcium phosphate. nis~hosphonates are a relct3vely new class of drugs, that have been used in these diseases to inhibit both mineralization and bone resorption, following the recognition, that they are stable analogs of endogenous pyrophosphate, which is a physiological inhibitor of calcification and bone resorption. A number of geminal bisphosphonates, namely, Pamidronate (ABP), Etidronate (HEBP), and Clodronate (ClMBP), have been approved for clinical use.

Rearrangement and Fragmentation Reactions of α-Hydroxyiminophoshinates. On the Nature of the Metaphosphonate Intermediate Involved in Phosphonylations by α-Hydroxyiminophosphinate

Abstract α-Hydroxyiminophosphonates are of interest on the one hand because of their potential to serve as metal chelators,1 and on the other hand because they have been shown to act as phosphorylating agents.2 As a consequence we have been studying the chemical and physical properties of various types of α-hydroxyiminophosphorus compounds.

Sigmatropic 1.5-hydrogen shift and concomitant cyclopropane bond cleavage on thermolysis of trans-1-isopropenyl-4-methylene spiro[2.x]alkanes into 1-methylene-(3′-methylbut-2′-enyl)-cycloalk-2-enes

Abstract Thermolysis of several trans -1-isopropenyl-4-methylene- spiro [2.x]- alkanes (x = 4,5) in xylene solution at 130° causes quantitative rearrangement to 1-methylene-2-(3′-methylbut-2′-enyl)cycloalkanes ( 3 – 4 ).