In Vitro and In Vivo Inhibition of Hydroxyapatite Formation and Dissolution by Bisacylphosphonates and Bishydroxyiminophosphonates

Breuer, Eli; Golomb, Gershon; Hoffman, Amnon; Schlossman, Ada; Gelder, Joel M. Van; Saadeh, Hanan; Levi, M; Eitan, Yael

doi:10.1080/10426509308032385

Cited by 6 publications

(3 citation statements)

References 3 publications

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“…4 α-Hydroxyiminophosphonates have a range of potential applications including their use as fungicidal agents, 5 as a source of iminoxy radicals as possible spin probes in enzymic centres, 6 and as generators, in physiological conditions, of monomeric metaphosphates, 7 which are implicated in phosphoryl transfer in vivo. 8 Despite the fact that much of this interest in α-hydroxyiminophosphonates arises from their marked affinity for calcified tissues and bone metastases, 9 very little is known about their metal complexing abilities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and structural properties of metal complexes of dialkyl α-hydroxyiminophosphonates

Bligh

Choi

McGrath

et al. 2000

J. Chem. Soc., Dalton Trans.

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have been used to synthesise neutral metal complexes with nickel() [Ni(L 1-3,5 )Cl 2 ], cobalt() [Co(L 1-3,5 )Cl 2 ] and lanthanides (La III with L 1,2,5 , Pr III with L 1,2,4-7 , Nd III with L 5 , Gd III with L 2,5 and Dy III with L 2,5 ) the charge being balanced by anionic ligands chloride or nitrate. Included in this range are two 3-heptyl derivatives which have not previously been reported. All the metal complexes have been fully characterised by elemental analysis, IR, electronic and NMR spectroscopy and mass spectrometry. X-Ray crystallography has been used to establish the structure of six key metal complexes and one of the free ligands (L 3 ). Three different bonding modes have been established. The d-block metal chlorides consistently show symmetrical bidentate coordination in [ML 2 Cl 2 ], the lanthanide chlorides [ML 3 Cl 3 ] are all asymmetrically bidentate and monodentate coordination was observed in the neodymium nitrate complex [NdL 5 2 (NO 3 ) 3 (H 2 O)].

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Section: Introductionmentioning

confidence: 99%

Synthesis and structural properties of metal complexes of dialkyl α-hydroxyiminophosphonates

Bligh

Choi

McGrath

et al. 2000

J. Chem. Soc., Dalton Trans.

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“…The precipitation of calcium phosphates is of fundamental importance because of the involvement of phases such as hydroxyapatite (HAP), the most stable calcium phosphate phase, in diverse areas including pathological biomineral deposits resulting in problems such as dental calculus, arthritis, arteriosclerosis, and urinary calculi. − In addition, undesirable calcium phosphate precipitation is involved in some industrial scaling situations such as oil and gas production, water purification and energy production technology . The inhibition or even prevention of calcium phosphate formation by the addition of trace amounts of inhibitors is therefore of considerable interest.…”

Section: Introductionmentioning

confidence: 99%

Influence of Organic Phosphonates on Hydroxyapatite Crystal Growth Kinetics

et al. 1996

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Phosphonate additives have important applications both in biomineralization processes and in industrial mineral scale formation. The kinetics of crystal growth of hydroxyapatite (HAP) has been investigated in the presence of seven phosphonate additives: HEDP (hydroxyethylenediphosphonic acid), DETPMP (diethylenetriaminepenta(methylenephosphonic acid)), DHTPMP (dihexyltriaminepenta (methylenephosphonic acid)), AMP (aminotris(methylenephosphonic acid)), HDTMP (hexyldiaminetetra(methylenephosphonic acid)), EDTMP (ethylenediaminetetra(methylenephosphonic acid)), and DETMP (diaminoethoxytetra(methylenephosphonic acid)). The constant composition (CC) method, used in this study, enabled reliable crystal growth rate data to be obtained even when the reactions were appreciably inhibited. The experiments were performed at pH 7.40, ionic strength 0.15 mol L -1 (maintained with NaCl), and an HAP relative supersaturation, σ, of 5.5. The results indicate that traces of some phosphonates (e10 -6 mol L -1 ) are extremely effective in inhibiting crystal growth. Assuming that the adsorbed additives block discrete growth sites on the crystal surfaces, the kinetic results may be interpreted in terms of a Langmuir adsorption model yielding kinetic affinity constants. The order of inhibitory effectiveness, DETMP > EDTMP > DETPMP > HEDP g DHTPMP > HDTMP g AMP, reflects the ability of the phosphonates to bind to the apatite surfaces. ζ potential measurments of HAP surfaces in the presence of additives provide important corroboratory data for the interpretation of the crystal growth results.

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“…In previous papers it was reported from our laboratory that α,α‘-difunctionalized long-chain bisphosphonates such as bisacylphosphonates 1 and α,α‘-bishydroxyiminophosphonates 2 are biologically active in calcium-related disorders such as hydroxyapatite formation and dissolution. This is in contrast to alkane-α,ω-bisphosphonates which are devoid of any activity .…”

mentioning

confidence: 99%

Direct Approach to α-Hydroxyphosphonic and α,ω-Dihydroxyalkane-α,ω-bisphosphonic Acids by the Reduction of (Bis)acylphosphonic Acids

Chen

Breuer

1998

J. Org. Chem.

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Acylphosphonic and bisacylphosphonic acid sodium salts were directly reduced by sodium borohydride to the corresponding hydroxyphosphonates and dihydroxyalkanebisphosphonates. The solution conformation of the (bis)hydroxyphosphonic acid sodium salts, elucidated from the homonuclear and heteronuclear coupling constants of the proton adjacent to the hydroxy and the phosphonic groups, was identical with the solid-state conformation as determined for 1-hydroxy-2-phenylethylphosphonic acid, a representative compound, by X-ray crystallography.In previous papers it was reported from our laboratory that R,R′-difunctionalized long-chain bisphosphonates such as bisacylphosphonates 1 1 and R,R′-bishydroxyiminophosphonates 2 2 are biologically active in calciumrelated disorders such as hydroxyapatite formation and dissolution. This is in contrast to alkane-R,ω-bisphosphonates which are devoid of any activity. 3 To elucidate the roles of the functional groups in R positions for biological activity, we have undertaken a systematic study of synthesizing variously difunctionalized longchain bisphosphonates. This paper describes the development of a practical method for the synthesis of R,ωdihydroxyalkane-R,ω-bisphosphonic acids 3 which are also suitable for the synthesis of simple R-hydroxyphosphonic acids 5.R-Hydroxyphosphonate esters have been obtained previously by the Abramov and Pudovik reactions which consist of adding phosphites to carbonyl compounds 4 or by the reduction of acylphosphonate diesters using various reducing agents. Thus dialkyl acylphosphonates have been reduced to R-hydroxyphosphonates by sodium borohydride, 5,6 aluminum isopropoxide, 7 activated zinc in acetic acid, 7a diborane in tetrahydrofuran, 8 and by lithium triethylborodeuteride. 9 Attempted synthesis of R,ω-dihydroxyalkane-R,ω-bisphosphonic acids 3 by reduction of tetramethyl bisacylphosphonates to the corresponding dihydroxyalkanebisphosphonate tetramethyl esters, followed by bromotrimethylsilane-induced demethylation to the corresponding bisphosphonic acids, gave rise in our hands to impure products which were difficult to purify because of their highly polar nature.We considered that since both acylphosphonic and R-hydroxyphosphonic acids, as well as their salts, are far more stable than the esters 10 (R-hydroxyphosphonate diesters fragment easily to the corresponding carbonyl compound by eliminating dialkyl hydrogen phosphonate 7 ), direct reduction of bisacylphosphonic acids might lead to the desired R-hydroxy and R,R′-dihydroxyalkane-R,ω-bisphosphonic acids more efficiently.

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In Vitro and In Vivo Inhibition of Hydroxyapatite Formation and Dissolution by Bisacylphosphonates and Bishydroxyiminophosphonates

Cited by 6 publications

References 3 publications

Synthesis and structural properties of metal complexes of dialkyl α-hydroxyiminophosphonates

Synthesis and structural properties of metal complexes of dialkyl α-hydroxyiminophosphonates

Influence of Organic Phosphonates on Hydroxyapatite Crystal Growth Kinetics

Direct Approach to α-Hydroxyphosphonic and α,ω-Dihydroxyalkane-α,ω-bisphosphonic Acids by the Reduction of (Bis)acylphosphonic Acids

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