Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of trypanosoma cruzi farnesyl diphosphate synthase

Journal of Medicinal Chemistry

Volumn 55, Issue 14, 2012, Pages 6445-6454

  Aripirala, Srinivas ^a   Szajnman, Sergio H ^c   Jakoncic, Jean ^b   Rodriguez, Juan B ^c   Docampo, Roberto ^d   Gabelli, Sandra B ^a   Amzel, L Mario ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b BROOKHAVEN NATIONAL LABORATORY   (United States)

^c UNIVERSIDAD DE BUENOS AIRES   (Argentina)

^d UNIVERSITY OF GEORGIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALKYL GROUP; ALLYL COMPOUND; AMINE; ANTITRYPANOSOMAL AGENT; BISPHOSPHONIC ACID DERIVATIVE; GERANYLTRANSFERASE; GERANYLTRANSFERASE INHIBITOR; ISOPRENOID; METHYL GROUP; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; CHAGAS DISEASE; CHEMICAL BOND; COMPLEX FORMATION; CONFORMATION; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG PROTEIN BINDING; DRUG SYNTHESIS; ENTHALPY; ENTROPY; ENZYME ACTIVE SITE; ENZYME INHIBITION; HYDROPHOBICITY; IC 50; ISOTHERMAL TITRATION CALORIMETRY; NONHUMAN; STRUCTURE ACTIVITY RELATION; THERMODYNAMICS; TRYPANOSOMA CRUZI; X RAY CRYSTALLOGRAPHY;

CALORIMETRY; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; ENZYME INHIBITORS; GERANYLTRANSTRANSFERASE; MAGNESIUM; MODELS, MOLECULAR; PHOSPHONIC ACIDS; PROTEIN CONFORMATION; THERMODYNAMICS; TRYPANOSOMA CRUZI;

EID: 84864209728     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300425y     Document Type: Article

References (66)

1. Urbina, J. A.; Docampo, R. Specific chemotherapy of Chagas disease: controversies and advances Trends Parasitol. 2003, 19, 495-501
2. Tropical Diseases; World Health Organization: Geneva; http://www.who.int/topics/tropical-diseases/en/.
3. Brener, Z. Biology of Trypanosoma cruzi Annu. Rev. Microbiol. 1973, 27, 347-382
4. Kirchhoff, L. V. American trypanosomiasis (Chagas' disease)-a tropical disease now in the United States N. Engl. J. Med. 1993, 329, 639-644
5. Galel, S. A.; Kirchhoff, L. V. Risk factors for Trypanosoma cruzi infection in California blood donors Transfusion 1996, 36, 227-231
6. Urbina, J. A. Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches Acta Trop. 2010, 115, 55-68
7. Roelofs, A. J.; Thompson, K.; Ebetino, F. H.; Rogers, M. J.; Coxon, F. P. Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages Curr. Pharm. Des. 2010, 16, 2950-2960
8. Reszka, A. A.; Rodan, G. A. Nitrogen-containing bisphosphonate mechanism of action Mini Rev. Med. Chem. 2004, 4, 711-719
9. Russell, R. G.; Rogers, M. J. Bisphosphonates: from the laboratory to the clinic and back again Bone 1999, 25, 97-106
10. Reszka, A. A.; Rodan, G. A. Mechanism of action of bisphosphonates Curr. Osteoporos Rep. 2003, 1, 45-52
11. Fleisch, H.; Russell, R. G.; Straumann, F. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis Nature 1966, 212, 901-903
12. 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, 1262-1264
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, 1264-1266
14. Urbina, J. A.; Moreno, B.; Vierkotter, S.; Oldfield, E.; Payares, G.; Sanoja, C.; Bailey, B. N.; Yan, W.; Scott, D. A.; Moreno, S. N.; Docampo, R. Trypanosoma cruzi contains major pyrophosphate stores, and its growth in vitro and in vivo is blocked by pyrophosphate analogs J. Biol. Chem. 1999, 274, 33609-33615
15. Hughes, D. E.; Wright, K. R.; Uy, H. L.; Sasaki, A.; Yoneda, T.; Roodman, G. D.; Mundy, G. R.; Boyce, B. F. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo J. Bone Miner. Res. 1995, 10, 1478-1487
16. Rogers, M. J.; Frith, J. C.; Luckman, S. P.; Coxon, F. P.; Benford, H. L.; Monkkonen, J.; Auriola, S.; Chilton, K. M.; Russell, R. G. Molecular mechanisms of action of bisphosphonates Bone 1999, 24, 73S-79S
17. 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. U.S.A 2006, 103, 7829-7834
18. Hosfield, D. J.; Zhang, Y.; Dougan, D. R.; Broun, A.; Tari, L. W.; Swanson, R. V.; Finn, J. Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis J. Biol. Chem. 2004, 279, 8526-8529
19. 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 ChemMedChem 2006, 1, 267-273
20. Cheng, F.; Oldfield, E. Inhibition of isoprene biosynthesis pathway enzymes by phosphonates, bisphosphonates, and diphosphates J. Med. Chem. 2004, 47, 5149-5158
21. Dunford, J. E.; Thompson, K.; Coxon, F. P.; Luckman, S. P.; Hahn, F. M.; Poulter, C. D.; Ebetino, F. H.; Rogers, M. J. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates J. Pharmacol. Exp. Ther. 2001, 296, 235-242
22. van Beek, E.; Pieterman, E.; Cohen, L.; Lowik, C.; Papapoulos, S. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates Biochem. Biophys. Res. Commun. 1999, 264, 108-111
23. Coxon, F. P.; Thompson, K.; Rogers, M. J. Recent advances in understanding the mechanism of action of bisphosphonates Curr. Opin. Pharmacol. 2006, 6, 307-312
24. Sanders, J. M.; Ghosh, S.; Chan, J. M.; Meints, G.; Wang, H.; Raker, A. M.; Song, Y.; Colantino, A.; Burzynska, A.; Kafarski, P.; Morita, C. T.; Oldfield, E. Quantitative structure-activity relationships for gammadelta T cell activation by bisphosphonates J. Med. Chem. 2004, 47, 375-384
25. Reddy, R.; Dietrich, E.; Lafontaine, Y.; Houghton, T. J.; Belanger, O.; Dubois, A.; Arhin, F. F.; Sarmiento, I.; Fadhil, I.; Laquerre, K.; Ostiguy, V.; Lehoux, D.; Moeck, G.; Parr, T. R., Jr.; Rafai Far, A. Bisphosphonated benzoxazinorifamycin prodrugs for the prevention and treatment of osteomyelitis ChemMedChem 2008, 3, 1863-1868
26. Forlani, G.; Giberti, S.; Berlicki, L.; Petrollino, D.; Kafarski, P. Plant P5C reductase as a new target for aminomethylenebisphosphonates J. Agric. Food Chem. 2007, 55, 4340-4347
27. Clezardin, P.; Massaia, M. Nitrogen-containing bisphosphonates and cancer immunotherapy Curr. Pharm. Des. 2010, 16, 3007-2014
28. Miller, K.; Erez, R.; Segal, E.; Shabat, D.; Satchi-Fainaro, R. Targeting bone metastases with a bispecific anticancer and antiangiogenic polymer-alendronate-taxane conjugate Angew. Chem., Int. Ed. Engl. 2009, 48, 2949-2954
29. Zhang, Y.; Cao, R.; Yin, F.; Hudock, M. P.; Guo, R. T.; Krysiak, K.; Mukherjee, S.; Gao, Y. G.; Robinson, H.; Song, Y.; No, J. H.; Bergan, K.; Leon, A.; Cass, L.; Goddard, A.; Chang, T. K.; Lin, F. Y.; Van Beek, E.; Papapoulos, S.; Wang, A. H.; Kubo, T.; Ochi, M.; Mukkamala, D.; Oldfield, E. Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation J. Am. Chem. Soc. 2009, 131, 5153-5162
30. Coleman, R. E. Risks and benefits of bisphosphonates Br. J. Cancer 2008, 98, 1736-1740
31. Docampo, R.; Moreno, S. N. The acidocalcisome as a target for chemotherapeutic agents in protozoan parasites Curr. Pharm. Des. 2008, 14, 882-888
32. Oldfield, E. Targeting isoprenoid biosynthesis for drug discovery: bench to bedside Acc. Chem. Res. 2010, 43, 1216-1226
33. Ghosh, S.; Chan, J. M.; Lea, C. R.; Meints, G. A.; Lewis, J. C.; Tovian, Z. S.; Flessner, R. M.; Loftus, T. C.; Bruchhaus, I.; Kendrick, H.; Croft, S. L.; Kemp, R. G.; Kobayashi, S.; Nozaki, T.; Oldfield, E. Effects of bisphosphonates on the growth of Entamoeba histolytica and Plasmodium species in vitro and in vivo J. Med. Chem. 2004, 47, 175-187
34. Martin, M. B.; Grimley, J. S.; Lewis, J. C.; Heath, H. T., III; Bailey, B. N.; Kendrick, H.; Yardley, V.; Caldera, A.; Lira, R.; Urbina, J. A.; Moreno, S. N.; Docampo, R.; Croft, S. L.; Oldfield, E. Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: a potential route to chemotherapy J. Med. Chem. 2001, 44, 909-916
35. Yardley, V.; Khan, A. A.; Martin, M. B.; Slifer, T. R.; Araujo, F. G.; Moreno, S. N.; Docampo, R.; Croft, S. L.; Oldfield, E. In vivo activities of farnesyl pyrophosphate synthase inhibitors against Leishmania donovani and Toxoplasma gondii Antimicrob. Agents Chemother. 2002, 46, 929-931
36. Bouzahzah, B.; Jelicks, L. A.; Morris, S. A.; Weiss, L. M.; Tanowitz, H. B. Risedronate in the treatment of Murine Chagas' disease Parasitol. Res. 2005, 96, 184-187
37. Martin, M. B.; Sanders, J. M.; Kendrick, H.; de Luca-Fradley, K.; Lewis, J. C.; Grimley, J. S.; Van Brussel, E. M.; Olsen, J. R.; Meints, G. A.; Burzynska, A.; Kafarski, P.; Croft, S. L.; Oldfield, E. Activity of bisphosphonates against Trypanosoma brucei rhodesiense J. Med. Chem. 2002, 45, 2904-2914
38. Rosso, V. S.; Szajnman, S. H.; Malayil, L.; Galizzi, M.; Moreno, S. N.; Docampo, R.; Rodriguez, J. B. Synthesis and biological evaluation of new 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase Bioorg. Med. Chem. 2011, 19, 2211-2217
39. Szajnman, S. H.; Bailey, B. N.; Docampo, R.; Rodriguez, J. B. Bisphosphonates derived from fatty acids are potent growth inhibitors of Trypanosoma cruzi Bioorg. Med. Chem. Lett. 2001, 11, 789-792
40. Szajnman, S. H.; Garcia Linares, G. E.; Li, Z. H.; Jiang, C.; Galizzi, M.; Bontempi, E. J.; Ferella, M.; Moreno, S. N.; Docampo, R.; Rodriguez, J. B. Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl diphosphate synthase Bioorg. Med. Chem. 2008, 16, 3283-3290
41. Szajnman, S. H.; Montalvetti, A.; Wang, Y.; Docampo, R.; Rodriguez, J. B. Bisphosphonates derived from fatty acids are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase Bioorg. Med. Chem. Lett. 2003, 13, 3231-3235
42. Szajnman, S. H.; Ravaschino, E. L.; Docampo, R.; Rodriguez, J. B. Synthesis and biological evaluation of 1-amino-1,1-bisphosphonates derived from fatty acids against Trypanosoma cruzi targeting farnesyl pyrophosphate synthase Bioorg. Med. Chem. Lett. 2005, 15, 4685-4690
43. Ling, Y.; Sahota, G.; Odeh, S.; Chan, J. M.; Araujo, F. G.; Moreno, S. N.; Oldfield, E. Bisphosphonate inhibitors of Toxoplasma gondii growth: in vitro, QSAR, and in vivo investigations J. Med. Chem. 2005, 48, 3130-3140
44. Laskovics, F. M.; Krafcik, J. M.; Poulter, C. D. Prenyltransferase. Kinetic studies of the 1′-4 coupling reaction with avian liver enzyme J. Biol. Chem. 1979, 254, 9458-9463
45. Laskovics, F. M.; Poulter, C. D. Prenyltransferase; determination of the binding mechanism and individual kinetic constants for farnesylpyrophosphate synthetase by rapid quench and isotope partitioning experiments Biochemistry 1981, 20, 1893-1901
46. Poulter, C. D.; Argyle, J. C.; Mash, E. A. Farnesyl pyrophosphate synthetase. Mechanistic studies of the 1′-4 coupling reaction with 2-fluorogeranyl pyrophosphate J. Biol. Chem. 1978, 253, 7227-7233
47. Ding, V. D.; Sheares, B. T.; Bergstrom, J. D.; Ponpipom, M. M.; Perez, L. B.; Poulter, C. D. Purification and characterization of recombinant human farnesyl diphosphate synthase expressed in Escherichia coli Biochem. J. 1991, 275 (Pt 1) 61-65
48. Gabelli, S. B.; McLellan, J. S.; Montalvetti, A.; Oldfield, E.; Docampo, R.; Amzel, L. M. Structure and mechanism of the farnesyl diphosphate synthase from Trypanosoma cruzi: implications for drug design Proteins 2006, 62, 80-88
49. Ohnuma, S.; Nakazawa, T.; Hemmi, H.; Hallberg, A. M.; Koyama, T.; Ogura, K.; Nishino, T. Conversion from farnesyl diphosphate synthase to geranylgeranyl diphosphate synthase by random chemical mutagenesis J. Biol. Chem. 1996, 271, 10087-10095
50. Tarshis, L. C.; Proteau, P. J.; Kellogg, B. A.; Sacchettini, J. C.; Poulter, C. D. Regulation of product chain length by isoprenyl diphosphate synthases Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 15018-15023
51. Narita, K.; Ohnuma, S.; Nishino, T. Protein design of geranyl diphosphate synthase. Structural features that define the product specificities of prenyltransferases J. Biochem. 1999, 126, 566-571
52. 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, 888-899
53. Szajnman, S. H.; Linares, G. G.; Moro, P.; Rodriguez, J. B. New insights into the chemistry of gem -bis(phosphonates): Unexpected rearrangement of Michael-type acceptors Eur. J. Org. Chem. 2005, 3687-3696
54. Degenhardt, C. R.; Burdsall, D. C. Synthesis of Ethenylidenebis(Phosphonic Acid) and Its Tetraalkyl Esters J. Org. Chem. 1986, 51, 3488-3490
55. Lazzarato, L.; Rolando, B.; Lolli, M. L.; Tron, G. C.; Fruttero, R.; Gasco, A.; Deleide, G.; Guenther, H. L. Synthesis of NO-donor bisphosphonates and their in vitro action on bone resorption J. Med. Chem. 2005, 48, 1322-1329
56. 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: Struct., Funct., Bioinf. 2010, 78, 888-899.
57. Otwinowski, Z.; Minor, W. Processing of X-ray diffraction data collected in oscillation mode Macromol. Crystallogr., Part A 1997, 276, 307-326
58. Winn, M. D.; Isupov, M. N.; Murshudov, G. N. Use of TLS parameters to model anisotropic displacements in macromolecular refinement Acta Crystallogr., Sect. D: Biol. Crystallogr. 2001, 57, 122-133
59. Murshudov, G. N.; Skubak, P.; Lebedev, A. A.; Pannu, N. S.; Steiner, R. A.; Nicholls, R. A.; Winn, M. D.; Long, F.; Vagin, A. A. REFMAC5 for the refinement of macromolecular crystal structures Acta Crystallogr., Sect. D: Biol. Crystallogr. 2011, 67, 355-367
60. Bailey, S. The Ccp4 Suite-Programs for Protein Crystallography Acta Crystallogr., Sect. D: Biol. Crystallogr. 1994, 50, 760-763
61. Navaza, J. Amore-An Automated Package for Molecular Replacement Acta Crystallogr., Sect. A: Found. Crystallogr. 1994, 50, 157-163
62. Emsley, P.; Lohkamp, B.; Scott, W. G.; Cowtan, K. Features and development of Coot Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 486-501
63. Laskowski, R. A.; Macarthur, M. W.; Moss, D. S.; Thornton, J. M. Procheck-A Program to Check the Stereochemical Quality of Protein Structures J. Appl. Crystallogr. 1993, 26, 283-291
64. Hooft, R. W.; Vriend, G.; Sander, C.; Abola, E. E. Errors in protein structures Nature 1996, 381, 272
65. Hooft, R. W. W.; Sander, C.; Vriend, G. Verification of protein structures: side-chain planarity J. Appl. Crystallogr. 1996, 29, 714-716
66. Kraulis, P. J. Molscript-A Program to Produce Both Detailed and Schematic Plots of Protein Structures J. Appl. Crystallogr. 1991, 24, 946-950