The chemistry of bisphosphonates: From antiscaling agents to clinical therapeutics

Anti-Cancer Agents in Medicinal Chemistry

Volumn 12, Issue 2, 2012, Pages 95-101

  Widler, Leo ^a   Jahnke, Wolfgang ^a   Green, Jonathan R ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Alendronate; Bisphosphonate; Farnesyl pyrophosphate synthase; Ibandronate; Pamidronate; Zoledronic acid

Indexed keywords

ADENOSINE TRIPHOSPHATE; ALENDRONIC ACID; BISPHOSPHONIC ACID DERIVATIVE; CALCIUM PHOSPHATE; CARBON; CLODRONIC ACID; ETIDRONIC ACID; GERANYLTRANSFERASE; HYDROLASE; HYDROXYAPATITE; HYDROXYL GROUP; IBANDRONIC ACID; INCADRONIC ACID; MINODRONIC ACID; NERIDRONIC ACID; NITROGEN; OLPADRONIC ACID; OXYGEN; PAMIDRONIC ACID; PYROPHOSPHATE; RISEDRONIC ACID; TILUDRONIC ACID; ZOLEDRONIC ACID;

ANTINEOPLASTIC ACTIVITY; ARTICLE; BODY FLUID; BONE DISEASE; BONE TUMOR; CALCIFICATION; CYTOTOXICITY; DISSOLUTION; DRUG MECHANISM; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; GASTROINTESTINAL TRACT; HUMAN; HYDROLYSIS; LUNG CANCER; MOLECULAR INTERACTION; MULTIPLE MYELOMA; NONHUMAN; OSSIFICATION; OSSIFYING MYOSITIS; OSTEOLYSIS; POSTMENOPAUSE OSTEOPOROSIS; UROGENITAL TRACT CANCER;

EID: 84856285895     PISSN: 18715206     EISSN: 18755992     Source Type: Journal    
DOI: 10.2174/187152012799014959     Document Type: Article

References (60)

1. Jastrzab, R.; Lomozik, L., Stability and coordination mode of complexes of polyphosphates and polymetaphosphates with copper(II) ions in aqueous solution-potentiometric, spectral and theoretical studies. J. Solution Chem., 2010, 39(7), 909-919.
2. Fleisch, H.; Russell, R. G.; Bisaz, S.; Casey, P. A.; Muhlbauer, R. C. The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution. Calcif. Tissue Res., 1968, (suppl), 10-10a.
3. Menshutkin, N., Ueber die Einwirkung des Chloracetyls auf phosphorige Säure. Annalen der Chemie und Pharmacie, 1865, 133, 317-320.
4. Blomen, L. J. M. J., History of the bisphosphonates: discovery and history of the non-medical uses of bisphosphonates. In: Bisphosphonate on Bones; Bijvoet, O. L. M.; Fleisch, H. A.; Canfield, R. E.; Russell, R. G. G., Eds. Elsevier: Amsterdam, 1995; pp. 111-124.
5. Russell, R. G.; Bisaz, S.; Donath, A.; Morgan, D. B.; Fleisch, H., Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta, and other disorders of bone. J. Clin. Invest., 1971, 50(5), 961-969.
6. Fleisch, H.; Bisaz, S., Mechanism of calcification: inhibitory role of pyrophosphate. Nature, 1962, 195, 911.
7. Fleisch, H.; Bisaz, S., Isolation from urine of pyrophosphate, a calcification inhibitor. Am. J. Physiol., 1962, 203, 671-675.
8. Russell, R.G.G., Bisaz, S., Fleisch, H., Currey, H.L.F., Rubinstein, H.M., Dietz, A.A., Boussina, I., Micheli, A., Fallet, G., Inorganic pyrophosphate in plasma, urine, and synovial fluid of patients with pyrophosphate arthropathy (chondrocalcinosis or pseudogout). Lancet, 1970, 2(7679), 899-902.
9. Fleisch, H.; Russell, R. G.; Straumann, F., Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature, 1966, 212(5065), 901-903.
10. Fleisch, H.; Maerki, J.; Russell, R. G., Effect of pyrophosphate on dissolution of hydroxyapatite and its possible importance in calcium homeostasis. Proc. Soc. Exp. Biol. Med., 1966, 122(2), 317-320.
11. Schibler, D.; Russell, R. G.; Fleisch, H., Inhibition by pyrophosphate and polyphosphate of aortic calcification induced by vitamin D3 in rats. Clin. Sci., 1968, 35(2), 363-372.
12. Jung, A.; Bisaz, S.; Fleisch, H., The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calcif. Tissue Res., 1973, 11(4), 269-280.
13. Francis, M. D.; Russell, R. G.; Fleisch, H., Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo. Science, 1969, 165(899), 1264-1266.
14. Fleisch, H.; Russell, R. G.; Francis, M. D., Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science, 1969, 165(899), 1262-1264.
15. Fleisch, H. A.; Russell, R. G.; Bisaz, S.; Muhlbauer, R. C.; Williams, D. A., The inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur. J. Clin. Invest., 1970, 1(1), 12-18.
16. Russell, R. G.; Croucher, P. I.; Rogers, M. J., Bisphosphonates: pharmacology, mechanisms of action and clinical uses. Osteoporos. Int., 1999, 9(suppl 2), S66-S80.
17. Sunberg, R. J.; Ebetino, F. H.; Mosher, C. T.; Roof, C. F., Designing drugs for stronger bones. CHEMTECH, 1991, 21(5), 304-309.
18. Van Beek, E.; Lowik, C.; Que, I.; Papapoulos, S., Dissociation of binding and antiresorptive properties of hydroxybisphosphonates by substitution of the hydroxyl with an amino group. J. Bone Miner. Res., 1996, 11(10), 1492-1497.
19. Lawson, M. A.; Xia, Z.; Barnett, B. L.; Triffitt, J. T.; Phipps, R. J.; Dunford, J. E.; Locklin, R. M.; Ebetino, F. H.; Russell, R. G., Differences between bisphosphonates in binding affinities for hydroxyapatite. J. Biomed. Mater. Res. B Appl. Biomater., 2010, 92(1), 149-155.
20. Lehenkari, P. P.; Kellinsalmi, M.; Napankangas, J. P.; Ylitalo, K. V.; Monkkonen, J.; Rogers, M. J.; Azhayev, A.; Vaananen, H. K.; Hassinen, I. E., Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol. Pharmacol., 2002, 61(5), 1255-1262.
21. Roelofs, A.; Ebetome, F. H.; Reszka, A. A.; Russell, R. G. G.; Rogers, M. J., Bisphosphonates: mechanisms of action. In: Principles of Bone Biology; 3rd ed.; Bilezikian, J. P.; Raisz, L. G.; Martin, T. J., Eds. Elsevier: Amsterdam, 2008; Vol. 2, pp. 1737-1767.
22. Russell, R. G.; Watts, N. B.; Ebetino, F. H.; Rogers, M. J., Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos. Int., 2008, 19(6), 733-759.
23. Breuil, V., Mechanisms of action of bisphosphonates. Rev. Rhum. Engl. Ed., 1999, 66(6), 339-343.
24. Rogers, M. J., New insights into the molecular mechanisms of action of bisphosphonates. Curr. Pharm. Des., 2003, 9(32), 2643-2658.
25. Rondeau, J. M.; Bitsch, F.; Bourgier, E.; Geiser, M.; Hemmig, R.; Kroemer, M.; Lehmann, S.; Ramage, P.; Rieffel, S.; Strauss, A.; Green, J. R.; Jahnke, W., Structural basis for the exceptional in vivo efficacy of bisphosphonate drugs. Chem. Med. Chem., 2006, 1(2), 267-273.
26. Ebetino, F.; Bayless, A.; Amburgey, J.; Ibbotson, K.; Danserau, S.; Ebrahimpour, A., Elucidation of a pharmacore for the bisphosphonate mechanism of bone antiresroptive activity. Phosphorus Sulfur Silicon, 1996, 109-110, 217-220.
27. Geddes, A. D.; D'Souza, S. M.; Ebetino, F. H.; Ibbotson, K. J., Bisphosphonates: structure-activity relationship and therapeutic implications. In: Bone and Mineral Research; Heersche, J. N. M.; Kanis, J. A., Eds. Elsevier Science: Amsterdam, 1994; Vol. 8, pp. 265-306.
28. Widler, L.; Jaeggi, K. A.; Glatt, M.; Muller, K.; Bachmann, R.; Bisping, M.; Born, A. R.; Cortesi, R.; Guiglia, G.; Jeker, H.; Klein, R.; Ramseier, U.; Schmid, J.; Schreiber, G.; Seltenmeyer, Y.; Green, J. R., Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa). J. Med. Chem., 2002, 45(17), 3721-3738.
29. Russell, R. G.; Muhlbauer, R. C.; Bisaz, S.; Williams, D. A.; Fleisch, H., The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatite in vitro and on bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomised rats. Calcif. Tissue Res., 1970, 6(3), 183-196.
30. Kavanagh, K. L.; Guo, K.; Dunford, J. E.; Wu, X.; Knapp, S.; Ebetino, F. H.; Rogers, M. J.; Russell, R. G.; Oppermann, U., The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc. Natl. Acad. Sci. USA, 2006, 103(20), 7829-7834.
31. Bassett, C. A.; Donath, A.; Macagno, F.; Preisig, R.; Fleisch, H.; Francis, M. D., Diphosphonates in the treatment of myositis ossificans. Lancet, 1969, 2(7625), 845.
32. Swislocki, A. L.; Wexler, J. A., The stumble-from pipe cleaner to bone builder. Endocr. Pract., 2007, 13(2), 194-197.
33. Russell, R. G., Bisphosphonates: from bench to bedside. Ann. N Y Acad. Sci., 2006, 1068, 367-401.
34. Francis, M. D.; Valent, D., Historical perspectives on the clinical development of bisphosphonates in the treatment of bone diseases. J. Musculoskelet. Neuronal Interact., 2008, 7(1), 2-8.
35. Boyce, B. F.; Smith, L.; Fogelman, I.; Johnston, E.; Ralston, S.; Boyle, I. T., Focal osteomalacia due to low-dose diphosphonate therapy in Paget's disease. Lancet, 1984, 1(8381), 821-824.
36. Ebetino, F. H.; Dansereau, S. M., Bisphosphonates antiresorptive structure-activity relationships. In: Bisphosphonates on Bones; Bijvoet, O. L. M.; Fleisch, H. A.; Canfield, R. E.; Russell, R. G. G., Eds. Elsevier Publishing Co.: Amsterdam, 1995; pp. 139-153.
37. Sietsema, W. K.; Ebetino, F. H.; Salvagno, A. M.; Bevan, J. A., Antiresorptive dose-response relationships across three generations of bisphosphonates. Drugs Exp. Clin. Res., 1989, 15(9), 389-396.
38. Shinoda, H.; Adamek, G.; Felix, R.; Fleisch, H.; Schenk, R.; Hagan, P., Structure-activity relationships of various bisphosphonates. Calcif. Tissue Int., 1983, 35(1), 87-99.
39. Devold, H. M.; Doung, G. M.; Tverdal, A.; Furu, K.; Meyer, H. E.; Falch, J. A.; Sogaard, A. J., Prescription of anti-osteoporosis drugs during 2004-2007-a nationwide register study in Norway. Eur. J. Clin. Pharmacol., 2010, 66(3), 299-306.
40. Hollingworth, S. A.; Gunanti, I.; Nissen, L. M.; Duncan, E. L., Secondary prevention of osteoporosis in Australia: analysis of government-dispensed prescription data. Drugs Aging, 2010, 27(3), 255-264.
41. Muhlbauer, R. C.; Bauss, F.; Schenk, R.; Janner, M.; Bosies, E.; Strein, K.; Fleisch, H., BM 21.0955, a potent new bisphosphonate to inhibit bone resorption. J. Bone Miner. Res., 1991, 6(9), 1003-1011.
42. Pataki, A.; Muller, K.; Green, J. R.; Ma, Y. F.; Li, Q. N.; Jee, W. S., Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: a comparative histomorphometric study on the cancellous bone formed before, during, and after treatment. Anat. Rec., 1997, 249(4), 458-468.
43. Takeuchi, M.; Sakamoto, S.; Kawamuki, K.; Kurihara, H.; Nakahara, H.; Isomura, Y., Studies on novel bone resorption inhibitors. II. Synthesis and pharmacological activities of fused aza-heteroarylbisphosphonate derivatives. Chem. Pharm. Bull. (Tokyo), 1998, 46(11), 1703-1709.
44. Takeuchi, M.; Sakamoto, S.; Yoshida, M.; Abe, T.; Isomura, Y., Studies on novel bone resorption inhibitors. I. Synthesis and pharmacological activities of aminomethylenebisphosphonate derivatives. Chem. Pharm. Bull. (Tokyo), 1993, 41(4), 688-693.
45. Green, J. R.; Seltenmeyer, Y.; Jaeggi, K. A.; Widler, L., Renal tolerability profile of novel, potent bisphosphonates in two shortterm rat models. Pharmacol. Toxicol., 1997, 80(5), 225-230.
46. Giraudo, E.; Inoue, M.; Hanahan, D., An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J. Clin. Invest., 2004, 114(5), 623-633.
47. Melani, C.; Sangaletti, S.; Barazzetta, F. M.; Werb, Z.; Colombo, M. P., Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res., 2007, 67(23), 11438-11446.
48. Roelofs, A. J.; Jauhiainen, M.; Monkkonen, H.; Rogers, M. J.; Monkkonen, J.; Thompson, K., Peripheral blood monocytes are responsible for gammadelta T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br. J. Haematol., 2009, 144(2), 245-250.
49. Roelofs, A. J.; Coxon, F. P.; Ebetino, F. H.; Lundy, M. W.; Henneman, Z. J.; Nancollas, G. H.; Sun, S.; Blazewska, K. M.; Bala, J. L.; Kashemirov, B. A.; Khalid, A. B.; McKenna, C. E.; Rogers, M. J., Fluorescent risedronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivo. J. Bone Miner. Res., 2010, 25(3), 606-616.
50. Wasko, B. M.; Dudakovic, A.; Hohl, R. J., Bisphosphonates induce autophagy by depleting geranylgeranyl diphosphate. J. Pharmacol. Exp. Ther., 2011, 337(2), 540-546.
51. Huang, C. H.; Gabelli, S. B.; Oldfield, E.; Amzel, L. M., Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer. Proteins, 2010, 78(4), 888-899.
52. Varela, I.; Pereira, S.; Ugalde, A. P.; Navarro, C. L.; Suarez, M. F.; Cau, P.; Cadinanos, J.; Osorio, F. G.; Foray, N.; Cobo, J.; de Carlos, F.; Levy, N.; Freije, J. M.; Lopez-Otin, C., Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat. Med., 2008, 14(7), 767-772.
53. Singh, A. P.; Zhang, Y.; No, J. H.; Docampo, R.; Nussenzweig, V.; Oldfield, E., Lipophilic bisphosphonates are potent inhibitors of Plasmodium liver-stage growth. Antimicrob. Agents Chemother., 2010, 54(7), 2987-2993.
54. Monkkonen, H.; Auriola, S.; Lehenkari, P.; Kellinsalmi, M.; Hassinen, I. E.; Vepsalainen, J.; Monkkonen, J., A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br. J. Pharmacol., 2006, 147(4), 437-445.
55. Dunford, J. E.; Kwaasi, A. A.; Rogers, M. J.; Barnett, B. L.; Ebetino, F. H.; Russell, R. G.; Oppermann, U.; Kavanagh, K. L., Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: timedependent inhibition of human farnesyl pyrophosphate synthase. J. Med. Chem., 2008, 51(7), 2187-2195.
56. Chen, K. M.; Hudock, M. P.; Zhang, Y.; Guo, R. T.; Cao, R.; No, J. H.; Liang, P. H.; Ko, T. P.; Chang, T. H.; Chang, S. C.; Song, Y.; Axelson, J.; Kumar, A.; Wang, A. H.; Oldfield, E., Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. J. Med. Chem., 2008, 51(18), 5594-5607.
57. Jahnke, W.; Rondeau, J. M.; Cotesta, S.; Marzinzik, A.; Pelle, X.; Geiser, M.; Strauss, A.; Gotte, M.; Bitsch, F.; Hemmig, R.; Henry, C.; Lehmann, S.; Glickman, J. F.; Roddy, T. P.; Stout, S. J.; Green, J. R., Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery. Nat. Chem. Biol., 2010, 6(9), 660-666.
58. Eidtmann, H.; de Boer, R.; Bundred, N.; Llombart-Cussac, A.; Davidson, N.; Neven, P.; von Minckwitz, G.; Miller, J.; Schenk, N.; Coleman, R., Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36- month results of the ZO-FAST Study. Ann. Oncol., 2010, 21(11), 2188-2194.
59. Coleman, R.; Cook, R.; Hirsh, V.; Major, P.; Lipton, A., Zoledronic acid use in cancer patients: more than just supportive care? Cancer, 2011, 117(1), 11-23.
60. Gnant, M.; Mlineritsch, B.; Stoeger, H.; Luschin-Ebengreuth, G.; Heck, D.; Menzel, C.; Jakesz, R.; Seifert, M.; Hubalek, M.; Pristauz, G.; Bauernhofer, T.; Eidtmann, H.; Eiermann, W.; Steger, G.; Kwasny, W.; Dubsky, P.; Hochreiner, G.; Forsthuber, E. P.; Fesl, C.; Greil, R., Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol., 2011, 12(7), 631-641.