Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II

Journal of Medicinal Chemistry

Volumn 56, Issue 16, 2013, Pages 6352-6370

  Raoof, Ali ^a   Depledge, Paul ^a   Hamilton, Niall M ^a   Hamilton, Nicola S ^a   Hitchin, James R ^a   Hopkins, Gemma V ^a   Jordan, Allan M ^a   Maguire, Laura A ^a   McGonagle, Alison E ^a   Mould, Daniel P ^a   Rushbrooke, Mathew ^b   Small, Helen F ^a   Smith, Kate M ^a   Thomson, Graeme J ^a   Turlais, Fabrice ^b   Waddell, Ian D ^a   Waszkowycz, Bohdan ^a   Watson, Amanda J ^a   Ogilvie, Donald J ^a  

^a UNIVERSITY OF MANCHESTER   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

(4 CHLOROPHENYL) 1,6 DIMETHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1 (CYCLOPROPYLMETHYL) 3 (4 ETHYLPHENYL) 6 METHYL 1 PROPYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1 BENZYL 3 (4 ETHYLPHENYL) 6 METHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1 CYCLOPROPYL 3 (4 ETHYLPHENYL) 6 METHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1 ETHYL 3 (4 ETHYLPHENYL) 6 METHYL 1 PROPYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1 ETHYL 3 (4 ETHYLPHENYL) 6 METHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1,6 DIMETHYL 3 (2 TOLYL)PYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1,6 DIMETHYL 3 (3 TOLYL)PYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1,6 DIMETHYL 3 (4 TOLYL)PYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1,6 DIMETHYL 3 [4 (TRIFLUOROMETHOXY)PHENYL]PYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1,6 DIMETHYL 3 [4 (TRIFLUOROMETHYL)PHENYL]PYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1,6 DIMETHYL 3 PHENETHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1,6 DIMETHYL 3 PHENYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1,6 DIMETHYL 3 PROPYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 1,6 DIMETHYL 3 TETRAHYDROPYRAN 4 YLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 3 (4 ETHYLPHENYL) 1 METHYL 6 PHENYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 3 (4 ETHYLPHENYL) 1 METHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 3 (4 ETHYLPHENYL) 1,6 DIMETHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 3 (4 ETHYLPHENYL) 6 METHYL 1 PHENYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 3 BENZYL 1,6 DIMETHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 3 CYCLOHEXYL 1,6 DIMETHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 3 CYCLOPENTYL 1,6 DIMETHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 3 CYCLOPROPYL 1,6 DIMETHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; 6 BENZYL 3 (4 ETHYLPHENYL) 1 METHYLPYRIMIDO[5,4 E][1,2,4]TRIAZINE 5,7 DIONE; DEAZAFLAVIN DERIVATIVE; PHOSPHODIESTERASE INHIBITOR; QUERCETIN DERIVATIVE; TYROSYL DNA PHOSPHODIESTERASE II INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; XANTHOTHRICIN DERIVATIVE;

ARTICLE; CELL MEMBRANE PERMEABILITY; CONTROLLED STUDY; DRUG HALF LIFE; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SOLUBILITY; DRUG STABILITY; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; HUMAN; IC 50; IN VITRO STUDY; LIVER MICROSOME METABOLISM; OXIDATION REDUCTION REACTION; STRUCTURE ACTIVITY RELATION;

PHOSPHORIC DIESTER HYDROLASES; PYRIMIDINONES; STRUCTURE-ACTIVITY RELATIONSHIP; TOPOISOMERASE II INHIBITORS; TRIAZINES;

EID: 84883141802     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm400568p     Document Type: Article

References (54)

1. Thomson, G.; Watson, A.; Caldecott, K.; Denneny, O.; Depledge, P.; Hamilton, N.; Hopkins, G.; Jordan, A.; Morrow, C.; Raoof, A.; Waddell, I.; Ogilvie, D. Generation of assays and antibodies to facilitate the study of human 5′-tyrosyl DNA phosphodiesterase Anal. Biochem. 2013, 436, 145-150
2. Cortes Ledesma, F.; El Khamisy, S. F.; Zuma, M. C.; Osborn, K.; Caldecott, K. A human 5′-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage Nature 2009, 461, 674-678
3. Moore, J. K.; Haber, J. E. Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae Mol. Cell. Biol. 1996, 16, 2164-2173
4. San Filippo, J.; Sung, P.; Klein, H. Mechanism of eukaryotic homologous recombination Annu. Rev. Biochem. 2008, 77, 229-257
5. Bahmad, K.; Nitiss, K. C.; Nitiss, J. L. UnTTrapping the ends: A new player in overcoming protein linked DNA damage Cell Res. 2010, 20, 122-123
6. Wei, H.; Ruthenburg, A. J.; Bechis, S. K.; Verdine, G. L. Nucleotide-dependent domain movement in the ATPase domain of a human type IIA DNA topoisomerase J. Biol. Chem. 2005, 280, 37041-37047
7. Wu, C.; Li, T.; Farh, L.; Lin, L.; Lin, T.; Yu, Y.; Yen, T.; Chiang, C.; Chan, N. Structural Basis of Type II Topoisomerase Inhibition by the Anticancer Drug Etoposide Science 2011, 333, 459-462
8. Moreland, J.; Gramada, A.; Buzko, O.; Zhang, Q.; Bourne, P. The Molecular Biology Toolkit (MBT): A modular platform for developing molecular visualization applications BMC Bioinf. 2005, 6 21
9. De Luchi, D.; Tereshko, V.; Gouyette, C.; Subirana, J. A. Structure of the DNA coiled coil formed by d(CGATATATATAT) ChemBioChem 2006, 7, 585-587
10. Pouliot, J. J.; Yao, K. C.; Robertson, C. A.; Nash, H. A. Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes Science 1999, 286, 552-555
11. Wilson, D. M., III; Barsky, D. The major human abasic endonuclease: Formation, consequences and repair of abasic lesions in DNA Mutat. Res. 2001, 485, 283-307
12. Sirivolu, V. R.; Kumar, S.; Vernekar, V.; Marchand, C.; Naumova, A.; Cherugi, A.; Renaud, A.; Stephen, A. G.; Chen, F.; Sham, Y. Y.; Pommier, Y.; Wang, Z. 5-Arylidenethioxothiazolidinones as Inhibitors of Tyrosyl-DNA Phosphodiesterase I J. Med. Chem. 2012, 55, 8671-8684
13. Coenye, T.; Vandamme, P., Eds. Burkholderia: Molecular Microbiology and Genomics; Horizon Bioscience: Norfolk, U.K., 2007; pp 153-177.
14. Daves, G. D.; Robins, R. K.; Cheng, C. C. Antibiotics. I. Synthesis of 1,6-Dimethyl-5,7-dioxo-1,5,6,7-tetrahydropyrimido [5,4- e ] as -triazine (toxoflavin) and related Compounds J. Am. Chem. Soc. 1962, 84, 1724-1729
15. Wei, W.; Chua, M.-S.; Grepper, S.; So, S. Small molecule antagonists of Tcf4/β-catenin complex inhibit the growth of HCC cells in vitro and in vivo Int. J. Cancer 2010, 126, 2426-2436
16. Showalter, H. D.; Turbiak, A. J.; Fearon, E. R.; Bommer, G. T. Pyrimidotriazinediones and pyrimidopyrimidinediones and methods of using the same. International Patent WO 2011166144, 2010.
17. Petry, S.; Barimghaus, K.-H.; Tennagels, N.; Guenter, M. Pyrimido[5,4-e][1,2,4]triazine-5,7-diones, methods for producing the same and their use. International Patent WO 20047737144, 2004.
18. Lacrampe, J. F.; Connors, R. W.; Ho, C. Y.; Richardson, A.; Freyne, E. J.; Buijnsters, P. J.; Bakker, A. N. 3-furanyl analogs of toxoflavine as kinase inhibitors. International Patent WO 20047241763, 2004.
19. Essayan, D. M. Cyclic nucleotide phosphodiesterases J. Allergy Clin. Immunol. 2001, 108, 671-680
20. Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design J. Med. Chem. 2011, 54, 2529-2591
21. Jaenchen, R.; Schonheit, P.; Thauer, R. K. Studies on the biosynthesis of coenzyme F420 in methanogenic bacteria Arch. Microbiol. 1984, 137, 362-365
22. Yoneda, F.; Sasaki, T. Preparation of 5-deazaflavin compounds as anticancer agents. Jpn. Kokai Tokkyo Koho, JP 199103081276 A 19910405, 1991.
23. Weissman, A. M.; Vousden, K. H.; Jensen, J. P.; Yang, Y.; Fang, S.; Woods, D.; Kenten, J. H.; Davydov, L.; Safiran, Y. J.; Oberoi, P. Deazaflavin compounds and methods of use thereof. International Patent WO 2004073615 A2 20040902, 2004.
24. Todorovic, N.; Giacomelli, A.; Hassell, J. A.; Frampton, C. S.; Capretta, A. Microwave-assisted synthesis of 3-aryl-pyrimido[5,4- e ][1,2,4]triazine-5, 7(1 H,6 H)-dione libraries: derivatives of toxoflavin Tetrahedron Lett. 2010, 51, 6037-6040
25. Chen, Y.; Barber, J. R.; Ng, S. C.; Zhou, Y. Parallel synthesis of novel 3-substituted 1-ethyl-6-methylpyrimido[4,5-c]pyridazine-5,7(1H,6H)-dione analogs Synth. Commun. 2010, 40, 821-832
26. Prins, L. H. A.; Petzer, J. P.; Malan, S. F. Synthesis and in vitro evaluation of pteridine analogues as monoamine oxidase B and nitric oxide synthase inhibitors Bioorg. Med. Chem. 2009, 17, 7523-7530
27. Styles, V. L.; Morrison, R. W. Pyrimido[4,5-]pyridazines. Cyclizations with α-Keto Acids J. Org. Chem. 1982, 47, 585-587
28. Danter, W.; Threlfall, C.; Guizzetti, S.; Marin, J. Compounds and method for treatment of HIV. International Patent WO 2011120153, 2011.
29. Whitteck, J. T.; Ni, W.; Griffin, B. M.; Eliot, A. C.; Thomas, P. M.; Kelleher, N. L.; Metcalf, W. W.; van der Donk, W. A. Reassignment of the structure of the antibiotic A53868 reveals an unusual amino dehydrophosphonic acid Angew. Chem., Int. Ed. 2007, 46, 9089-9092
30. Bey, E.; Marchais-Oberwinkler, S.; Werth, R.; Negri, M.; Al-Soud, Y. A.; Kruchten, P.; Oster, A.; Frotscher, M.; Birk, B.; Hartmann, R. W. Design, synthesis, biological evaluation and pharmacokinetics of bis(hydroxyphenyl) substituted azoles, thiophenes, benzenes, and aza-benzenes as potent and selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) J. Med. Chem. 2008, 51, 6725-6739
31. King, J. A.; Keown, J.; McIlroy, J. W.; Armstrong, W. P.; McKervey, M. A.; McMordie, A. Di-steroidal prodrugs of estradiol. U.S. Patent US 20050159399 A1 20050721, 2005.
32. Arhin, F.; Bélanger, O.; Ciblat, S.; Dehbi, M.; Delorme, D.; Dietrich, E.; Dixit, D.; Lafontaine, Y.; Lehoux, D.; Liu, J.; McKay, G. A.; Moeck, G.; Reddy, R.; Rose, Y.; Srikumar, R.; Tanaka, K. S. E.; Williams, D. M.; Gros, P.; Pelletier, J.; Parr, T. R., Jr.; Far, A. R. A new class of small molecule RNA polymerase inhibitors with activity against Rifampicin-resistant Staphylococcus aureus Bioorg. Med. Chem. 2006, 14, 5812-5832
33. Quiroga, J.; Trilleras, J.; Insuasty, B.; Abonía, R.; Nogueras, M.; Marchal, A.; Cobo, J. A straightforward synthesis of pyrimido[4,5-b] quinoline derivatives assisted by microwave irradiation Tetrahedron Lett. 2010, 51 (7) 1107-1109
34. Wilson, J. M.; Henderson, G.; Black, F.; Sutherland, A.; Ludwig, R. L.; Vousden, K. H.; Robins, D. J. Synthesis of 5-deazaflavin derivatives and their activation of p53 in cells Bioorg. Med. Chem. 2007, 15 (1) 77-86
35. Yoneda, F.; Nagamatsu, T. A covenient synthesis of toxoflavins, toxflavin 4-oxides and 1-demethyltoxoflavins Chem. Pharm. Bull. 1975, 23, 2001-2009
36. Wempen, I.; Fox, J. J. Pyrimidines. II. Synthesis of 6-fluorouracil J. Med. Chem. 1964, 7 (4) 207-209
37. Baker, B. R.; Rzeszotarski, W. Irreversible enzyme inhibitors. CXXI. Thymidine phosphorylase. 9. Nature and dimensions of the hydrophobic bonding region J. Med. Chem. 1968, 11, 639-644
38. Wright, G. E.; Brown, N. C. Inhibitors of Bacillus subtilis DNA polymerase III. 6-Anilinouracils and 6-(alkylamino)uracils J. Med. Chem. 1980, 23, 34-38
39. Wright, G. E.; Gambino, J. J. Quantitative structure-activity relationships of 6-anilinouracils as inhibitors of Bacillus subtilis DNA polymerase III J. Med. Chem. 1984, 27, 181-185
40. McCaffrey, R.; Wright, G.; Baril, E. F. Composition and method for inhibiting terminal deoxyribonucleotidyl transferase activity in cancer chemotherapy. U.S. Patent 4,576,948 A, 1986.
41. Shinkai, S.; Kawase, A.; Yamaguchi, T.; Manabe, O.; Wada, Y.; Yoneda, F.; Ohta, Y.; Nishimoto, K. Coenzyme models. 47. Synthesis and reactivity studies of novel flavinophanes and 5-deazaflavinophanes: correlation between flavin reactivity and ring strain J. Am. Chem. Soc. 1989, 111, 4928-4935
42. Shinkai, S.; Yamaguchi, T.; Nakao, H.; Manabe, O. Synthesis of new deazaflavins with planar chirality. Redox-induced "rope-skipping" racemization Tetrahedron Lett. 1986, 27, 1611-1614
43. Brown, N. C.; Barnes, M. H.; Wright, G. E. Compounds destabilizing the zinc finger of the dnaE protein of Gram-positive bacteria and their use as antibiotics. International Patent WO 2000020556 A2, 2000.
44. Thomson, G. J.; Hamilton, N. S.; Hopkins, G. V.; Waddell, I. D.; Watson, A. J.; Ogilvie, D. J. A fluorescence based assay for the AP-site cleavage activity of human tyrosyl DNA phosphodiesterase 1 Anal. Biochem. 2013, 440, 1-5
45. Calculated log P determined using Dotmatics software (www.dotmatics.com).
46. Schrödinger Suite 2012, Schrödinger, LLC, New York, NY, 2012.
47. TorchV10, part of the Cresset software package, http://www.cresset-group. com/products/torch/
48. SparkV10, part of the Cresset software package, www.cresset-group.com/ products/spark/. The Spark uses a fragment database to suggest replacements for a user defined scaffold in order to identify moieties that reproduce the shape and electrostatic and hydrophobic properties of the parent compound.
49. Thorne, N.; Auld, D. S.; Inglese, J. Apparent activity in high-throughput screening: Origins of compound-dependent assay interference Curr. Opin. Chem. Biol. 2010, 14, 315-324
50. 2 by redox cycling in reducing environments Assay Drug Dev. Technol. 2010, 8, 152-174
51. Schellenberg, M. J.; Appel, C. D.; Adhikari, S.; Robertson, P. D.; Ramsden, D. A.; Williams, R. S. Mechanism of repair of 5′-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2 Nat. Struct. Mol. Biol. 2012, 19, 1363-1371
52. Shi, K.; Kurahashi, R. G.; Tsutakawa, S. E.; Tainer, J. A.; Pommier, Y.; Aihara, H. Structural basis for recognition of 5′-phosphotyrosine adducts by Tdp2 Nat. Struct. Mol. Biol. 2012, 19, 1372-1377
53. Nagamatsu, T.; Yamasaki, H. General syntheses of 1-alkyltoxoflavin and 8-alkylfervenulin derivatives of biological significance by the regioselective alkylation of reumycin derivatives and the rates of transalkylation from 1-alkyltoxoflavins into nucleophiles J. Chem. Soc., Perkin Trans. 2001, 1, 130-137
54. Blehaut, H.; Bellamy, F.; Matt, C.; Giraud, S.; Charre, D.; Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide. International Patent WO2010072807 (A2), 2010.