Design, synthesis and enzymatic evaluation of 6-bridged imidazolyluracil derivatives as inhibitors of human thymidine phosphorylase

Journal of Pharmacy and Pharmacology

Volumn 59, Issue 4, 2007, Pages 537-547

  McNally, Virginia A ^a   Rajabi, Mehdi ^a   Gbaj, Abdul ^a   Stratford, Ian J ^a   Edwards, Philip N ^a   Douglas, Kenneth T ^a   Bryce, Richard A ^a   Jaffar, Mohammed ^b   Freeman, Sally ^a  

^a UNIVERSITY OF MANCHESTER   (United Kingdom)

^b Morvus Technology Limited   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

5 BROMO 6 [(3 METHYLIMIDAZOL 1 YL)METHYL]URACIL CHLORIDE; ARGININE; GLYCOSYLTRANSFERASE INHIBITOR; HISTIDINE; IMIDAZOLE DERIVATIVE; IMIDAZOLYLURACIL; SERINE; THYMIDINE PHOSPHORYLASE; THYMIDINE PHOSPHORYLASE INHIBITOR; UNCLASSIFIED DRUG; DRUG DERIVATIVE; ENZYME INHIBITOR; URACIL;

ARTICLE; DRUG BINDING; DRUG CONFORMATION; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; BINDING SITE; CHEMICAL STRUCTURE; DRUG ANTAGONISM; HUMAN; IC 50; METABOLISM; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

BINDING SITES; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, MOLECULAR; STRUCTURE-ACTIVITY RELATIONSHIP; THYMIDINE PHOSPHORYLASE; URACIL;

EID: 34250206317     PISSN: 00223573     EISSN: None     Source Type: Journal    
DOI: 10.1211/jpp.59.4.0008     Document Type: Article

References (45)

1. Berg-Nielsen, K., Stensrud, T., Bernatek, E. (1972) Heterocyclics from malonyl chlorides. 3. Cyclization and oxidation of some 2-alkylthiopyrimidones. Acta Chem. Scand. 26: 947-951
2. Brown, N. S., Bicknell, R. (1998) Thymidine phosphorylase, 2-deoxy-D-ribose and angiogenesis. Biochem. J. 334: 1-8
3. Cole, C., Reigan, P., Gbaj, A., Edwards, P. N., Douglas, K. T., Stratford, I. J., Freeman, S., Jaffar, M. (2003) Potential tumor-selective nitroimidazolylmethyluracil prodrug derivatives: inhibitors of the angiogenic enzyme thymidine phosphorylase. J. Med. Chem. 46: 207-209
4. Cresswell, R. M., Wood, H. C. S. (1960) The biosynthesis of pteridines. 1. The synthesis of riboflavin. J. Chem. Soc. 4768-4775
5. Esteban-Gamboa, A., Balzarini, J., Esnouf, R., De Clercq, E., Camarasa, M. J., Perez Perez, M. J. (2000) Design, synthesis, and enzymatic evaluation of multisubstrate analogue inhibitors of Escherichia coli thymidine phosphorylase. J. Med. Chem. 43: 971-983
6. Ewing T. J. A., Makino S., Skillman A. G., Kuntz I. D. (2001) DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J. Comput.-Aided Mol. Des. 15: 411-428
7. Fukushima, M., Suzuki, N., Emura, T., Yano, S., Kazuno, H., Tada, Y., Yamada, Y., Asao, T. (2000) Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2′-deoxyribonucleosides. Biochem. Pharmacol. 59: 1227-1236
8. Gasteiger, J, Marsili, M. (1980) Iterative partial equalization of orbital electronegativity - a rapid access to atomic charges. Tetrahedron 36: 3219-3288
9. Gbaj, A., Edwards, P. N., Reigan, P., Freeman, S., Jaffar, M., Douglas, K. T. (2006) Thymidine phosphorylase from Escherichi coli: tight-binding inhibitors as enzyme active-site titrants. J. Enyzme Inhib. Med. Chem. 21: 69-73
10. Griffiths, L., Stratford, I. J. (1997) Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumour growth and response to therapy. Br. J. Cancer 76: 689-693
11. Griffiths, L., Stratford, I. J. (1998) The influence of elevated levels of platelet-derived endothelial cell growth factor/thymidine phosphorylase on tumourigenicity, tumour growth, and oxygenation. Int. J. Rad. Oncol. Biol. Phys. 42: 877-883
12. Halgren, T. A. (1996) Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J. Comput. Chem. 17: 490-512
13. Ishikawa, T., Sekiguchi, F., Fukase, Y., Sawada, N., Ishitsuka, H. (1998) Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res. 58: 685-690
14. Johnson, T. B. (1943) The reaction of hydrochloric acid with 6-methyl-5,5 dichloroxyhydrouracil. J. Am. Chem. Soc. 65: 1220-1222
15. Klein, R. S., Lenzi, M., Lim, T. H., Hotchkiss, K. A., Wilson, P., Schwartz, E. L. (2001) Novel 6-substituted uracil analogs as inhibitors of the angiogenic actions of thymidine phosphorylase. Biochem. Pharmacol. 62: 1257-1263
16. Kono, A, Hara, Y, Matsushima, Y. (1981) Enzymatic formation of 5-fluorouracil from 1-(tetrahydro-2-furanyl)-5-fluorouracil (Tegafur) in human-tumor tissues. Chem. Pharm. Bull. 29: 1486-1488
17. Kono, A., Hara, Y., Sugata, S., Karube, Y., Matsushima, Y., Ishitsuka H. (1983) Activation of 5′-deoxy-5-fluorouridine by thymidine phosphorylase in human tumors. Chem. Pharm. Bull. 31: 175-178
18. Krenitsky, T. A., Koszalka, G. W., Tuttle, J. V. (1981) Purine nucleoside synthesis: an efficient method employing nucleoside phosphorylases. Biochemistry 20: 3615-3621
19. Langen, P., Etzold, G., Barwolff, D., Preussel, B. (1967) Inhibition of thymidine phosphorylase by 6-aminothymine and derivatives of 6-aminouracil. Biochem. Pharmacol. 16: 1833-1837
20. Maeda, K., Kang, S. M., Ogawa, M., Onoda, N., Sawada, T., Nakata, B., Kato, Y., Chung, Y. S., Sowa, M. (1997) Combined analysis of vascular endomelial growth factor and platelet-derived endothelial cell growth factor expression in gastric carcinoma. Int. J. Cancer 74: 545-550
21. Marley, G. F., Plaut, G. W. E. (1959) The isolation, synthesis, and metabolic properties of 6,7-dimediyl-8-ribityllumazine. J. Biol. Chem. 234: 641-647
22. Matsushita, S., Nitanda, T., Furukawa, T., Sumizawa, T., Tani, A., Nishimoto, K., Akiba, S., Miyadera, K., Fukushima, M., Yamada, Y., Kanuki, T., Akiyame, S. (1999) The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors. Cancer Res. 59: 1911-1916
23. McNally, V. A., Gbaj, A., Douglas, K. T., Stratford, I. J., Jaffar, M., Freeman, S., Bryce, R. A. (2003) Identification of a novel class of inhibitor of human and Escherichia coli thymidine phosphorylase by in silico screening. Bioorg. Med. Chem. Lett. 13: 3705-3709
24. Miwa, M., Cook, A., Ishitsuka, H. (1986) Enzymatic cleavage of various fluorinated pyrimidine nucleosides to 5-fluorouracil and their antiproliferative activities in human and murine tumor-cells. Chem. Pharm. Bull. 34: 4225-4232
25. Murray, P. E., McNally, V. A., Lockyer, S. D., Williams, K. J., Stratford, I. J., Jaffar, M., Freeman, S. (2002) Synthesis and enzymatic evaluation of pyridinium substituted uracil derivatives as novel inhibitors of thymidine phosphorylase. Bioorg. Med. Chem. 10: 525-530
26. Nakayama, C., Wataya, Y., Meyer, R. B., Santi, D. V., Saneyoshi, M., Ueda, T. (1980) Thymidine phosphorylase. Substrate specificity for 5-substituted-2′-deoxyuridines. J. Med. Chem. 23: 962-964
27. Niemz, A., Imbriglio, J., Rotello, V. M. (1997) Model systems for flavoenzyme activity: one- and two-electron reduction of flavins in aprotic hydrophobic environments. J. Am. Chem. Soc. 119: 887-892
28. Norman, R. A., Barry, S. T., Bate, M., Breed, J., Colls, J. G., Ernill, R. J., Luke, R. W. A., Minshull, C. A., McAlister, M. S. B., McCall, E. J., McMiken, H. H. J., Paterson, D. S., Timms, D., Tucker, J. A., Pauptit, R. A. (2004) Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor. Structure 12: 75-84
29. O'Brien, T. S., Fox, S. B., Dickinson, A. J., Turley, H., Westwood, M., Moghaddam, A., Gatter, K. C., Bicknell, R., Harris, A. L. (1996) Expression of the angiogenic factor thymidine phosphorylase/ platelet-derived endothelial cell growth factor in primary bladder cancers. Cancer Res. 56: 4799-4804
30. Pan, B. C., Chen, Z. H., Chu, E., Chu, M. Y. W., Chu, S. H. (1998) Synthesis of 5-halogeno-6-amino-2′-deoxyuridines and their analogs as potential inhibitors of thymidine phosphorylase. Nucleosides Nucleotides 17: 2367-2382
31. Patterson, A. V., Zhang, H., Moghaddam, A., Bicknell, R., Talbot, C. D., Stratford, I. J., Harris, A. L. (1995) Increased sensitivity to the prodrug 5′-deoxy-5 fluorouridine with modulation of 5-fluoro-2′-deoxyuridine sensitivity in MCF-7 cells transfected with thymidine phosphorylase. Br. J Cancer 72: 669-675
32. Price, M. L. P., Guida, W. C., Jackson, T. E., Nydick, J. A., Gladstone, P. L., Juarez, J. C., Donate, F., Ternansky, R. J. (2003) Design of novel N-(2,4-dioxo-1,2,3,4 tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as thymidine phosphorylase inhibitors, and flexible docking to a homology model. Bioorg. Med. Chem. Lett. 13: 107-110
33. Priego, E. M., Mendieta, J., Gago, F., Balzarini, J., De Clercq, E., Camarasa, M. J., Perez-Perez, M. J. (2003) Towards new thymidine phosphorylase/PD-ECGF inhibitors based on the transition state of the enzyme reaction. Nucleosides Nucleotides Nucleic Acids 22: 951-953
34. Pugmire, M. J., Ealick S. E. (1998) The crystal structure of pyrimidine nucleoside phosphorylase in a closed conformation. Structure 6: 1467-1479
35. Reigan, P., Gbaj, A., Chinje, E., Stratford, I. J., Douglas, K. T., Freeman, S. (2004) Synthesis and enzymatic evaluation of xanthine oxidase-activated prodrugs based on inhibitors of thymidine phosphorylase. Bioorg. Med. Chem. Lett 14: 5247-5250
36. Reigan, P., Edwards, P. N., Gbaj, A., Cole, C., Barry, S. T., Page, K. M., Ashton, S. E., Luke, R. W. A., Douglas, K. T., Stratford, I. J., Jaffar, M., Bryce, R. A., Freeman, S. (2005) Aminoimidazolyl-methyluracil analogues as potent inhibitors of thymidine phosphorylase and their bioreductive nitroimidazolyl prodrugs. J. Med. Chem. 48: 392-402
37. Relf, M., LeJeune, S., Scott, P. A. E., Fox, S., Smith, K., Leek, R., Moghaddam, A., Whitehouse, R., Bicknell, R., Harris, A. L. (1997) Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 57: 963-969
38. Reynolds, K., Farzaneh, F., Collins, W. P., Campbell, S., Bourne, T. H., Lawton, F., Moghaddam, A., Harris, A. L., Bicknell, R. (1994) Association of ovarian malignancy with expression of platelet-derived endothelial-cell growth factor. J. Natl. Cancer Inst. 86: 1234-1238
39. Schwartz, E. L., Baptiste, N, O'Connor, C. J., Wadler, S., Otter, B. A. (1994) Potentiation of the antitumor activity of 5-fluorouracil in colon carcinoma cells by the combination of interferon and deoxyribonucleosides results from complementary effects on thymidine phosphorylase. Cancer Res. 54: 1472-1478
40. Shimabukuro, T., Matsuyama, H., Baba, Y., Jojima, K., Suyama, K. I., Aoki, A., Suga, A., Yamamoto, N., Naito, K. (2005) Expression of thymidine phosphorylase in human superficial bladder cancer. Int. J. Urol. 12: 29-34
41. Takao, S., Takebayashi, Y., Che, X. M., Shinchi, H., Natsugoe, S., Miyadera, K., Yamada, Y., Akiyama, S., Aikou, T. (1998) Expression of thymidine phosphorylase is associated with a poor prognosis in patients with ductal adenocarcinoma of the pancreas. Clin. Cancer Res. 4: 1619-1624
42. Takebayashi, Y., Akiyama, S., Akiba, S., Yamada, K., Miyadera, K., Sumizawa, T., Yamada, Y., Murata, F., Aikou, T. (1996) Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J. Natl Cancer Inst. 88: 1110-1117
43. Toi, M., Rahman, M. A., Bando, H., Chow, L. W. C. (2005) Thymidine phosphorylase (platelet-derived endothelial-cell growth factor) in cancer biology and treatment. Lancet Oncol. 6: 158-166
44. Yano, S., Kazuno, H., Suzuki, N., Emura, T., Wierzba, K., Yamashita, J., Tada, Y., Yamada, Y., Fukushima, M., Asao, T. (2004a) Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1: discovery of novel orally active inhibitors of human thymidine phosphorylase. Bioorg. Med. Chem. 12: 3431-3441
45. Yano, S., Kazuno, H., Sato, T., Suzuki, N., Emura, T., Wierzba, K., Yamashita, J., Tada, Y., Yamada, Y., Fukushima, M., Asao, T. (2004b) Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: Optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase. Bioorg. Med. Chem. 12: 3443-3450