The Design and Synthesis of Bone-Active Phosphinic Acid Analogues: 1. The Pyridylaminomethane Phosphonoalkylphosphinates

Ebetino, Frank H.; Jamieson, Laura

doi:10.1080/10426509008040673

Cited by 9 publications

(9 citation statements)

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“…The potencies of two BPs, NE97220 and NE21656 (N(5‐picolyl)‐aminomethane‐1,1‐bisphosphonic acid), were compared with those of their PAP analogs, in which one of the phosphonate hydroxyl groups is replaced by a methyl group 23 . In addition, the potency of NE97220 was compared with that of its BPI analog, in which a hydroxyl group on both phosphonate moieties is replaced by a methyl group 23 …”

Section: Resultsmentioning

confidence: 99%

“…Modifications to either or both of the phosphonate groups of the P‐C‐P moiety, such as replacement of a hydroxyl group with a methyl group or removal of one of the phosphonate groups, also reduces antiresorptive activity 22–25 . Although these changes to the phosphonate groups also result in lower affinity for bone mineral, 23 , 25 the reduction in antiresorptive potency cannot be accounted for entirely by the loss in affinity for bone 25 . Hence, the phosphonate groups, as well as the BP side chains, appear to be required for the molecular interaction of BPs with their pharmacological targets.…”

Section: Introductionmentioning

confidence: 99%

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Heterocycle-Containing Bisphosphonates Cause Apoptosis and Inhibit Bone Resorption by Preventing Protein Prenylation: Evidence from Structure-Activity Relationships in J774 Macrophages

Luckman

Coxon

Ebetino

et al. 1998

Journal of Bone and Mineral Research

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157

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Recent evidence suggests that bisphosphonates (BPs) may inhibit bone resorption by mechanisms that lead to osteoclast apoptosis. We have previously shown that BPs also reduce cell viability and induce apoptosis in the macrophage-like cell line J774. To determine whether BPs inhibit osteoclast-mediated bone resorption and affect J774 macrophages by the same molecular mechanism, we examined the potency to reduce J774 cell viability of pairs of nitrogen-containing BPs that differ slightly in the structure of the heterocycle-containing side chain but that differ markedly in antiresorptive potency. In all cases, the most potent antiresorptive BP of each pair also caused the greatest loss of J774 viability, while the less potent antiresorptive BPs were also less potent at reducing J774 cell viability. Similarly, the bisphosphinate, phosphonoalkylphosphinate and monophosphonate analogs of BPs (in which one or both phosphonate groups are modified, giving rise to much less potent or inactive antiresorptive agents) were much less potent or inactive at reducing J774 cell viability. Thus, the structure-activity relationships of BPs for inhibiting bone resorption match those for causing loss of cell viability in J774 cells, indicating that BPs inhibit osteoclast-mediated bone resorption and reduce J774 macrophage viability by the same molecular mechanism. Loss of J774 cell viability after treatment with BPs was associated with a parallel increase in apoptotic cell death. We have recently proposed that nitrogen-containing BPs reduce cell viability and cause J774 apoptosis as a consequence of inhibition of enzymes of the mevalonate pathway and hence loss of prenylated proteins. In this study, the BPs that were potent inducers of J774 apoptosis and potent antiresorptive agents were also found to be effective inhibitors of protein prenylation in J774 macrophages, whereas the less potent BP analogs did not inhibit protein prenylation. This provides strong evidence that BPs with a heterocyclic, nitrogencontaining side chain, such as risedronate, inhibit osteoclast-mediated bone resorption and induce J774 apoptosis by preventing protein prenylation. (J Bone Miner Res 1998;13:1668-1678)

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heterocycle-Containing Bisphosphonates Cause Apoptosis and Inhibit Bone Resorption by Preventing Protein Prenylation: Evidence from Structure-Activity Relationships in J774 Macrophages

Luckman

Coxon

Ebetino

et al. 1998

Journal of Bone and Mineral Research

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238

157

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“…In 1990, Ebetino et al described both a contiguous and stepwise strategy for the synthesis of the pyridylaminomethane-based class of phosphinylalkylphosphonates 3 (Fig. 2, R = Me or n -butyl, R 1 = H, R 2 = Py and its derivatives, R 3 , R 4 = H), and discovered the bone resorption-inhibition ability of these compounds [19–21]. They also registered a number of patents relating to methods for treating or preventing diseases characterised by abnormal calcium and phosphate metabolism by utilising 1-phosphinylalkylphosphonic acid derivatives, especially their 1-amino and 1-hydroxy derivatives, and their pharmaceutical compositions [22–27].…”

Section: Introductionmentioning

confidence: 99%

A new method for the synthesis of α-aminoalkylidenebisphosphonates and their asymmetric phosphonyl-phosphinyl and phosphonyl-phosphinoyl analogues

Kuźnik¹,

Mazurkiewicz²,

Grymel³

et al. 2015

Beilstein J. Org. Chem.

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SummaryA convenient approach has been developed to α-aminoalkylidenebisphosphonates and their asymmetric phosphonyl-phosphinyl and phosphonyl-phosphinoyl analogues by α-phosphonylation, α-phosphinylation or α-phosphinoylation of 1-(N-acylamino)alkylphosphonates, that, in turn, are easily accessible from N-acyl-α-amino acids. Effective electrophilic activation of the α-position of 1-(N-acetylamino)alkylphosphonates was achieved by electrochemical α-methoxylation of these compounds in methanol, mediated with NaCl, followed by displacement of the methoxy group with triphenylphosphonium tetrafluoroborate to give hitherto unknown 1-(N-acetylamino)-1-triphenylphosphoniumalkylphosphonate tetrafluoroborates. The latter compounds react smoothly with trialkyl phosphites, dialkyl phosphonites or alkyl phosphinites in the presence of Hünig’s base and methyltriphenylphosphonium iodide in a Michaelis–Arbuzov-like reaction to give the expected alkylidenebisphosphonates, 1-phosphinylalkylphosphonates or 1-phosphinoylalkylphosphonates, respectively, in good yields.

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“…1 Due to their biological significance, many synthetic methods have been developed for these products. [2][3][4][5][6][7][8] reported that it could be obtained from diethyl phosphite and POCl 3 at room temperature. 2 Degenhardt et al reported that these products could be obtained form dimethylchloroformiminium chloride with triethyl phosphite.…”

Section: Introductionmentioning

confidence: 99%

A Novel Synthesis of Alkylamino Substituted Methylenediphosphonates Using Bis(trichloromethyl) Carbonate and RCONR¹R²

Yu¹,

Wang

Chen

2008

Chin. J. Chem.

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The Design and Synthesis of Bone-Active Phosphinic Acid Analogues: 1. The Pyridylaminomethane Phosphonoalkylphosphinates

Cited by 9 publications

References 11 publications

Heterocycle-Containing Bisphosphonates Cause Apoptosis and Inhibit Bone Resorption by Preventing Protein Prenylation: Evidence from Structure-Activity Relationships in J774 Macrophages

Heterocycle-Containing Bisphosphonates Cause Apoptosis and Inhibit Bone Resorption by Preventing Protein Prenylation: Evidence from Structure-Activity Relationships in J774 Macrophages

A new method for the synthesis of α-aminoalkylidenebisphosphonates and their asymmetric phosphonyl-phosphinyl and phosphonyl-phosphinoyl analogues

A Novel Synthesis of Alkylamino Substituted Methylenediphosphonates Using Bis(trichloromethyl) Carbonate and RCONR¹R²

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The Design and Synthesis of Bone-Active Phosphinic Acid Analogues: 1. The Pyridylaminomethane Phosphonoalkylphosphinates

Cited by 9 publications

References 11 publications

Heterocycle-Containing Bisphosphonates Cause Apoptosis and Inhibit Bone Resorption by Preventing Protein Prenylation: Evidence from Structure-Activity Relationships in J774 Macrophages

Heterocycle-Containing Bisphosphonates Cause Apoptosis and Inhibit Bone Resorption by Preventing Protein Prenylation: Evidence from Structure-Activity Relationships in J774 Macrophages

A new method for the synthesis of α-aminoalkylidenebisphosphonates and their asymmetric phosphonyl-phosphinyl and phosphonyl-phosphinoyl analogues

A Novel Synthesis of Alkylamino Substituted Methylenediphosphonates Using Bis(trichloromethyl) Carbonate and RCONR1R2

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A Novel Synthesis of Alkylamino Substituted Methylenediphosphonates Using Bis(trichloromethyl) Carbonate and RCONR¹R²