Trisubstituted acridine derivatives as potent and selective telomerase inhibitors

Journal of Medicinal Chemistry

Volumn 46, Issue 21, 2003, Pages 4463-4476

  Harrison, R John ^a   Cuesta, Javier ^a   Chessari, Gianni ^a   Read, Martin A ^a   Basra, Sanji K ^a   Reszka, Anthony P ^a   Morrell, James ^a   Gowan, Sharon M ^a   Incles, Christopher M ^a   Tanious, Farial A ^b   Wilson, W David ^b   Kelland, Lloyd R ^a,c   Neidle, Stephen ^a  

^a IMPERIAL CANCER RESEARCH FUND   (United Kingdom)

^b GEORGIA STATE UNIVERSITY   (United States)

^c ST GEORGE'S UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

3,6 BIS(3 PYRROLIDIN 1 YLPROPIONAMIDO) 9 (2 AMINOPHENYLAMINO)ACRIDINE; ACRIDINE DERIVATIVE; TELOMERASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DNA STRUCTURE; DRUG DNA BINDING; DRUG SYNTHESIS; HUMAN; HUMAN CELL; MOLECULAR MODEL; STRUCTURE ACTIVITY RELATION; SURFACE PLASMON RESONANCE; TUMOR CELL;

ACRIDINES; CRYSTALLOGRAPHY, X-RAY; DNA; DNA, NEOPLASM; HUMANS; KINETICS; MAGNETIC RESONANCE SPECTROSCOPY; MODELS, MOLECULAR; MOLECULAR CONFORMATION; REVERSE TRANSCRIPTASE INHIBITORS; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RHODAMINES; STRUCTURE-ACTIVITY RELATIONSHIP; SURFACE PLASMON RESONANCE; TELOMERASE; TUMOR CELLS, CULTURED;

EID: 10744221442     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0308693     Document Type: Article

References (69)

1. n among Vertebrates. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 7049-7053.
2. (b) McElligott, R.; Wellinger, R. J. The Terminal DNA Structure of Mammalian Chromosomes. EMBO J. 1997, 16, 3705-3714.
3. Blackburn, E. H. Switching and Signalling at the Telomere. Cell 2001, 106, 661-673.
4. Bryan, T. M.; Cech, T. R. Telomerase and Maintenance of Chromosome Ends. Curr. Opin. Cell Biol. 1999, 11, 318-324.
5. (a) Harley, C. B.; Futcher, A. B.; Greider, C. W. Telomeres Shorten During Ageing of Human Fibroblasts. Nature 1990, 345, 458-460.
6. (b) Allsopp, R. C.; Harley, C. B. Evidence for a Critical Telomere Length in Senescent Human Fibroblasts. Exp. Cell Res. 1995, 219, 130-136.
7. (a) Kim, N. W.; Piatyszek, M. A.; Prowse, K. R.; Harley, C. B.; West, M. D.; Ho, P. L. C.; Coviello, G. M.; Wright, W. E.; Weinrich, R. L.; Shay, J. W. Specific Association of Human Telomerase Activity with Immortal Cells and Cancer. Science 1994, 266, 2011-2015.
8. (b) Counter, C. M.; Hirte, H. W.; Bacchetti, S.; Harley, C. B. Telomerase Activity in Human Ovarian Carcinoma. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2900-2904.
9. (c) Tang, R.; Cheng, A.-J.; Wang, J.-Y.; Wang, T.C. V. Close Correlation between Telomerase Expression and Adenomatous Polyp Progression in Multistep Colorectal Carcinogenesis. Cancer Res. 1998, 58, 4052-4054.
10. (d) Hoos, A.; Hepp, H. H.; Kaul, S.; Ahlert, T.; Bastert, G.; Wallwiener, D. Telomerase Activity Correlates with Tumor Aggressiveness and Reflects Therapy Effect in Breast Cancer. Int. J. Cancer 1998, 79, 8-12.
11. (e) Sano, T.; Asai, A.; Fujimaki, T.; Kirino, T. Telomerase Activity in 144 Brain Tumours. Br. J. Cancer 1998, 77, 1633-1637.
12. (f) Tomoda, R.; Seto, M.; Tsumuki, H.; Iida, K.; Yamazaki, T.; Sonoda, J.; Matsumine, A.; Uchida, A. Telomerase Activity and Human Telomerase Reverse Transcriptase mRNA Expression Are Correlated with Clinical Aggressiveness in Soft Tissue Tumours. Cancer 2002, 95, 1127-1133.
13. (a) Greider, C. W.; Blackburn, E. H. Identification of a Specific Telomere Terminal Transferase Activity in Tetrahymena Extracts. Cell 1985, 43, 405-413.
14. (b) Meyerson, M.; Counter, C. M.; Eaton, E. N.; Ellisen, L. W.; Steiner, P.; Caddle, S. D.; Ziaugra, L.; Beijersbergen, R. L.; Davidoff, M. J.; Liu, Q.; Bacchetti, S.; Haber, D. A.; Weinberg, R. A. hEST2, the Putative Human Telomerase Catalytic Subunit Gene, Is Up-regulated in Tumor Cells and During Immortalization. Cell 1997, 90, 785-795.
15. (c) Nakamura, T. M.; Morin, G. B.; Chapman, K. B.; Weinrich, S. L.; Andrews, W. H.; Lingner, J.; Harley, C. B.; Cech, T. R. Telomerase Catalytic Subunit Homologs from Fission Yeast and Human. Science 1997, 277, 955-959.
16. Counter, C. M.; Hahn, W. C.; Wei, W.; Caddle, S. D.; Beijersbergen, R. L.; Lansdorp, P. M.; Sedivy, J. M.; Weinberg, R. A. Dissociation among in Vitro Telomerase Activity, Telomere Maintenance and Cellular Immortalization. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 14723-14728.
17. (a) Bryan, T. M.; Englezou, A.; Dalla-Pozza, L.; Dunham, M. A.; Reddel, R. R. Evidence for an Alternative Mechanism for Maintaining Telomere Length in Human Tumors and Tumor-Derived Cell Lines. Nat. Med. 1997, 3, 1271-1274.
18. (b) Dunham, M. A.; Neumann, A. A.; Fasching, C. L.; Reddel, R. R. Telomere Maintenance by Recombination in Human Cells. Nat. Genet. 2000, 26, 447-450.
19. (a) Hahn, W. C.; Stewart, S. A.; Brooks, M. W.; York, S. G.; Eaton, E.; Kurachi, A.; Beijersbergen, R. L.; Knoll, J. H. M.; Meyerson, M.; Weinberg, R. A. Inhibition of Telomerase Limits the Growth of Human Cancer Cells. Nat. Med. 1999, 10, 1164-1170.
20. (b) Zhang, L.; Mar, V.; Zhou, W.; Harrington, L.; Robinson, M. O. Telomere Shortening and Apoptosis in Telomerase-Inhibited Human Tumor Cells. Genes Dev. 1999, 13, 2388-2399.
21. (a) Herbert, B. S.; Pitts, A. E.; Baker, S. I.; Hamilton, S. E.; Wright, W. E.; Shay, J. W.; Corey, D. R. Inhibition of Human Telomerase in Immortal Human Cells Leads to Progressive Telomere Shortening and Cell Death. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 14276-14281.
22. (b) Corey, D. R. Telomerase Inhibition, Oligonucleotides and Clinical Trials. Oncogene 2002, 21, 631-637.
23. (a) Damm, K.; Hemmann, U.; Garin-Chesa, P.; Hauel, N.; Kauffmann, I.; Priepke, H.; Niestroj, C.; Daiber, C.; Enenkel, B.; Guilliard, B.; Lauritsch, I.; Muller, E.; Pascolo, E.; Sauter, G.; Pantic, M.; Martens, U. M.; Wenz, C.; Lingner, J.; Kraut, N.; Rettig, W. J.; Schnapp, A. A Highly Selective Telomerase Inhibitor Limiting Human Cancer Cell Proliferation. EMBO J. 2001, 20, 6958-6968.
24. (b) Pascolo, E.; Wenz, C.; Lingner, J.; Hauel, N.; Priepke, H.; Kauffmann, I.; Garin-Chesa, P.; Rettig, W. J.; Damm, K.; Schnapp, A. Mechanism of Human Telomerase Inhibition by BIBR1532, a Synthetic, Non-nucleosidic Drug Candidate. J. Biol. Chem. 2002, 277, 15566-15572.
25. (a) White, L. K.; Wright, W. E.; Shay, J. W. Telomerase Inhibitors. Trends Biotechnol. 2001, 19, 114-120.
26. (b) Mergny, J.-L.; Riou, J.-F.; Maillet, P.; Teulade-Fichou, M.-P.; Gilson, E. Natural and Pharmacological Regulation of Telomerase. Nucleic Acids Res. 2002, 30, 839-865.
27. (c) Neidle, S.; Parkinson, G. N. Telomere Maintenance as a Target for Anticancer Drug Discovery. Nat. Rev. Drug Discovery 2002, 1, 383-393.
28. (d) Rezler, E. M.; Rearss, D. J.; Hurley, L. H. Telomeres and Telomerases as Drug Targets. Curr. Opin. Pharmacol. 2002, 2, 415-423.
29. (e) Shay, J. W.; Wright, W. E. Telomerase: A Target for Cancer Therapeutics. Cancer Cell 2002, 2, 257-265.
30. (a) Mergny, J.-L.; Hélène, C. G-Quadruplex DNA: A Target for Drug Design. Nat. Med. 1998, 4, 1366-1367.
31. (b) Han, H.; Hurley, L. H. G-Quadruplex DNA: A Potential Target for Anti-cancer Drug Design. Trends Pharmacol. Sci. 2000, 21, 136-142.
32. (c) Kerwin, S. M. G-Quadruplex DNA as a Target for Drug Design. Curr. Pharm. Des. 2000, 6, 441-478.
33. (d) Haider, S. M.; Parkinson, G. N.; Read, M. A.; Neidle, S. Design and Analysis of G4 Recognition Compounds. In DNA and RNA Binders; Bailly, C., Wilson, W. D., Eds.; John Wiley: Weinheim, Germany, 2002; pp 337-359.
34. Wright, W. E.; Tesmer, V. M.; Huffman, K. E.; Levene, S. D.; Shay, J. W. Normal Human Chromosomes Have Long G-Rich Telomeric Overhangs at One End. Genes Dev. 1997, 11, 2801-2809.
35. (a) Williamson, J. R. G-Quartet Structures in Telomeric DNA. Annu. Rev. Biophys. Biomol. Struct. 1994, 23, 703-730.
36. (b) Simonsson, T. G-Quadruplex DNA structures-Variations on a Theme. Biol. Chem. 2001, 382, 621-628.
37. Zahler, A. M.; Williamson, J. R.; Cech, T. R.; Prescott, D. M. Inhibition of Telomerase by G-Quartet DNA Structures. Nature 1991, 350, 718-720.
38. (a) Sun, D.; Thompson, B.; Cathers, B. E.; Salazar, M.; Kerwin, S. M.; Trent, J. O.; Jenkins, T. C.; Neidle, S.; Hurley, L. H. Inhibition of Human Telomerase by a G-Quadruplex-Interactive Compound. J. Med. Chem. 1997, 40, 2113-2116.
39. (b) Perry, P. J.; Gowan, S. M.; Reszka, A. P.; Polucci, P.; Jenkins, T. C.; Kelland, L. R.; Neidle, S. 1,4- and 2,6-Di-substituted Amidoanthracene-9,10-dione Derivatives as Inhibitors of Human Telomerase. J. Med. Chem. 1998, 41, 3253-3260.
40. (c) Perry, P. J.; Reszka, A. P.; Wood, A. A.; Read, M. A.; Gowan, S. M.; Dosanjh, H. S.; Trent, J. O.; Jenkins, T. C.; Kelland, L. R.; Neidle, S. Human Telomerase Inhibition by Regioisomeric Di-substituted Amidoanthracene-9,10-diones. J. Med. Chem. 1998, 41, 4873-4884.
41. Perry, P. J.; Read, M. A.; Davies, R. T.; Gowan, S. M.; Reszka, A. P.; Wood, A. A.; Kelland, L. R.; Neidle, S. 2,7-Di-substituted Amidofluorenone Derivatives as Inhibitors of Human Telomerase. J. Med. Chem. 1999, 42, 2679-2684.
42. (a) Harrison, R. J.; Gowan, S. M.; Kelland, L. R.; Neidle, S. Human Telomerase Inhibition by Substituted Acridine Derivatives, Bioorg. Med. Chem. Lett. 1999, 9, 2463-2468.
43. (b) Read, M. A.; Wood, A. A.; Harrison, J. R.; Gowan, S. M.; Kelland, L. R.; Dosanjh, H. S.; Neidle, S. Molecular Modelling Studies on G-Quadruplex Complexes of Telomerase Inhibitors: Structure-Activity Relationships. J. Med. Chem. 1999, 42, 4538-4546.
44. (a) Wheelhouse, R.; Sun, D.; Han, H.; Han, F. X.; Hurley, L. H. Cationic Porphyrins as Telomerase Inhibitors: The Interaction of Tetra-(N-methyl-4-pyridyl)porphine with Quadruplex DNA. J. Am. Chem. Soc. 1998, 120, 3261-3262.
45. (b) Han, F. X.; Wheelhouse, R. T.; Hurley, L. H. Interactions of TMPyP4 and TMPyP2 with Quadruplex DNA. Structural Basis for the Differential Effects on Telomerase Inhibition. J. Am. Chem. Soc. 1999, 121, 3561-3570.
46. (c) Shi, D. F.; Wheelhouse, R. T.; Sun, D.; Hurley, L. H. Quadruplex-Interactive Agents as Telomerase Inhibitors: Synthesis of Porphyrins and Structure-Activity Relationships for the Inhibition of Telomerase. J. Med. Chem. 2001, 44, 4509-4523.
47. (a) Federoff, O. V.; Salazar, M.; Han, H.; Chemeris, V. V.; Kerwin, S. M.; Hurley, L. H. NMR-Based Model of a Telomerase-Inhibiting Compound Bound to G-Quadruplex DNA. Biochemistry 1998, 37, 12367-12374.
48. (b) Heald, R. A.; Modi, C.; Cookson, J. C.; Hutchinson, I.; Laughton, C. A.; Gowan, S. M.; Kelland, L. R.; Stevens, M. F. G. Antitumor polycyclic acridines. 8. Synthesis and Telomerase-Inhibitory Activity of Methylated Pentacyclic Acridinium Salts. J. Med. Chem. 2002, 45, 590-597.
49. (a) Mergny, J.-L.; Lacroix, L.; Teulade-Fichou, M.-P.; Hounsou, C.; Guittal, L.; Hoarau, M.; Arimondo, P. B.; Vigneron, J.-P.; Lehn, J.-M.; Riou, J.-F.; Garestier, T.; Hélène, C. Telomerase Inhibitors Based on Quadruplex Ligands Selected by a Fluorescence Assay. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 3062-3067.
50. (b) Riou, J.-F.; Guittat, L.; Mailliet, P.; Laoui, A.; Renou, E.; Petitgenet, O.; Mégnin-Chanet, F.; Hélène, C.; Mergny, J.-L. Cell Senescence and Telomere Shortening Induced by a New Series of Specific G-Quadruplex DNA Ligands. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 2672-2677.
51. (a) Caprio, V.; Guyen, B.; Opoku-Boahen, Y.; Mann, J.; Gowan, S. M.; Kelland, L. M.; Read, M. A.; Neidle, S. A Novel Inhibitor of Human Telomerase Derived from 10H-Indolo[3,2-b]quinoline. Bioorg. Med. Chem. Lett. 2000, 10, 2063-2066.
52. (b) Alberti, P.; Schmitt, P.; Nguyen, C.-H.; Rivalle, C.; Hoarau, M.; Grierson, D. S.; Mergny, J.-L. Benzoindoloquinolines Interact with DNA Tetraplexes and Inhibit Telomerase. Bioorg. Med. Chem. Lett. 2002, 12, 1071-1074.
53. Shin-ya, K.; Wierzba, K.; Matsuo, K.; Ohtani, T.; Yamada, Y.; Furihata, K.; Hayakawa, Y.; Seto, H. Telomestatin, a Novel Telomerase Inhibitor from Streptomyces anulatus. J. Am. Chem. Soc. 2001, 123, 1262-1263.
54. Kim, M. Y.; Vankayalapati, H.; Shin-ya, K.; Wierzba, K.; Hurley, L. H. Telomestatin, a Potent Telomerase Inhibitor That Interacts Quite Specifically with the Human Telomeric Intramolecular G-Quadruplex. J. Am. Chem. Soc. 2002, 124, 2098-2099.
55. Denny, W. A.; Cain, B. F.; Atwell, G. J.; Hansch, C.; Panthananickal, A. ; Leo, A. Potential Antitumor agents. 36. Quantitative Relationships between Experimental Antitumor Activity, Toxicity, and Structure for the General Class of 9-Anilinoacridine Antitumor Agents. J. Med. Chem. 1982, 25, 276-315.
56. Read, M. A.; Harrison, R. J.; Romagnoli, B.; Tanious, F. A.; Gowan, S. H.; Reszka, A. P.; Wilson, W. D.; Kelland, L. R.; Neidle, S. Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 4844-4849.
57. Gowan, S. M.; Harrison, J. R.; Patterson, L.; Valenti, M.; Read, M. A.; Neidle, S.; Kelland, L. R. A G-quadruplex-interactive potent small molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. Mol. Pharmacol. 2002, 61, 1154-1162.
58. Parkinson, G. N.; Lee, M. H. P.; Neidle, S. Crystal Structure of Parallel Quadruplexes from Human Telomeric DNA. Nature 2002, 417, 876-880.
59. 3] G-Tetraplex. Structure 1993, 1, 263-282.
60. Kelland, L. R.; Abel, G.; McKeage, M. J.; Jones, M.; Goddard, P. M.; Valenti, M.; Murrer, B. A.; Harrap, K. R. Preclinical Antitumor Evaluation of Bis-acetato-amine-dichloro-cyclohexylamine Platinum(IV): An Orally Active Platinum Drug. Cancer Res. 1993, 53, 2581-2586.
61. Gowan, S. M.; Heald, R.; Stevens, M. F. G.; Kelland, L. R. Potent Inhibition of Telomerase by Small-Molecule Pentacyclic Acridines Capable of Interacting with G-Quadruplexes. Mol. Pharmacol. 2001, 60, 981-988.
62. Li, G.-Z.; Eller, M. S.; Firoozabadi, R.; Gilchrest, B. A. Evidence That Exposure of the Telomere 3′ Overhang Sequence Induces Senescence. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 527-531.
63. Hemann, M. T.; Strong, M. A.; Hao, L. Y.; Greider, C. W. The Shortest Telomere, Not Average Telomere Length, Is Critical for Cell Viability and Chromosome Stability. Cell 2001, 107, 67-77.
64. Chang, S.; Khoo, C. M.; Naylor, M. L.; Maser, R. S.; DePinho, R. A. Telomere-Based Crisis: Functional Differences between Telomerase Activation and ALT in Tumor Progression. Genes Dev. 2003, 17, 88-100.
65. Gavathiotis, E.; Heald, R. A.; Stevens, F. G.; Searle, M. S. Recognition and Stabilization of Quadruplex DNA by a Potent New Telomerase Inhibitor: NMR Studies of the 2:1 Complex of a Pentacyclic Methylacridinium Cation with d(TTAGGGT)4. Angew. Chem., Int. Ed. 2001, 40, 4749-4751.
66. Haider, S. M.; Parkinson, G. N.; Neidle, S. Structure of a G-Quadruplex-Ligand Complex. J. Mol. Biol. 2003, 326, 117-125.
67. Clark, G. R.; Pytel, P. D.; Squire, C. J.; Neidle, S. Structure of the first parallel DNA quadruplex-drug complex. J. Am. Chem. Soc. 2003, 125, 4066-4067.
68. INSIGHTII Modelling Environment; Molecular Simulations Inc.: San Diego, CA, 1999.
69. Luty, B. A.; Wasserman, Z. R.; Stouten, P. F. W.; Hodge, C. N.; Zacharias, M.; McCammon, J. A. A Molecular Mechanics/Grid Method for Evaluation of Ligand-Receptor Interactions. J. Comput. Chem. 1995, 16, 454-464.