Triazole nucleoside derivatives bearing aryl functionalities on the nucleobases show antiviral and anticancer activity

Mini-Reviews in Medicinal Chemistry

Volumn 10, Issue 9, 2010, Pages 806-821

  Xia, Y ^a,b   Qu, F ^b   Peng, L ^a  

^a AIX MARSEILLE UNIVERSITÉ   (France)

^b WUHAN UNIVERSITY   (China)

Author keywords

HCV; Nucleoside analogs; Pancreatic cancer; TMV; Triazole nucleosides

Indexed keywords

ANTINEOPLASTIC AGENT; ANTIVIRUS AGENT; NUCLEOSIDE; TRIAZOLE DERIVATIVE;

CHEMISTRY; DRUG DESIGN; HEPATITIS C; HUMAN; NEOPLASMS; SYNTHESIS;

ANTINEOPLASTIC AGENTS; ANTIVIRAL AGENTS; DRUG DESIGN; HEPATITIS C; HUMANS; NEOPLASMS; NUCLEOSIDES; TRIAZOLES;

EID: 77956565351     PISSN: 13895575     EISSN: None     Source Type: Journal    
DOI: 10.2174/138955710791608316     Document Type: Article

References (89)

1. Sidwell, R.W.; Huffman, J.H.; Khare, G.P. Allen, L.B. Witkowski, J.T. Robins, R.K. Broad-spectrum antiviral activity ofvirazole: 1--D-Ribofuranosyl-1,2,4-triazole-3- carboxamide. Science 1972, 177, 705-706.
2. Witkowski, J.T.; Robins, R.K.; Sid-well, R.W.; Simon, L.N. Design, synthesis, and broad spectrum an-tiviral activity of 1- -D-ribofuranosyl-1,2,4-triazole-3-carboxamideand related nucleosides. J. Med. Chem., 1972, 15, 1150-1154.
3. Streeter, D.G.; Witkowski, J.T.; Khare, G.P.; Sidwell, R.W.; Bauer, R.J. Robins, R.K. Simon, L.N. Mechanism of action of 1- -D-ribofuranosyl-1,2,4-triazole-3- carboxamide (Virazole), a newbroad-spectrum antiviral agent. Proc. Natl. Acad. Sci. USA, 1973,70, 1174-1178.
4. Schlosser, S.F.; Schuler, M.; Berg, C.P. Lauber, K. Schulze-Osthoff, K. Schmahl, F.W. Wesselborg, S. Ribavirin and alpha-interferon enhance death receptor-mediatedapoptosis and caspase activation in human hepatoma cells. Antimi-crob. Agents Chemother., 2003, 47, 1912-1921.
5. Herdewijn, P, Ed. Modified nucleosides in biochemistry, biotech-nology and medicine, WILEY-VCH Verlag GmbH & Co. KGaA:Weinheim, Germany, 2008.
6. Claire, S. Nucleoside mimetics: Their chemistry and biologicalproperties, Advanced Chemistry Texts, Gordon and Beach SciencePublishers, UK, 2001.
7. De Clercq, E.; Hol, A. Acyclic nucleoside phosphonates: a keyclass of antiviral drugs. Nat. Rev. Drug Discov., 2005, 4, 928-940.
8. De Clercq, E. The design of drugs for HIV and HCV. Nat. Rev.Drug Discov., 2007, 6, 1001-1018.
9. De Clercq, E. Antiviraldrugs in current clinical use. J. Clin. Virol., 2004, 30, 115-133.
10. Galmarini, C. M.; Popowycz, F., Joseph, B. Cytotoxic nucleosideanalogues: different strategies to improve their clinical efficacy.Curr. Med. Chem., 2008, 15, 1072-1082.
11. Galmarini, C.M. Mackey, J.R. Dumontet, C. Nucleoside analogues and nucleobasesin cancer treatment. Lancet Oncol., 2002, 3, 415-424.
12. Berdis, A.J. DNA polymerases as therapeutic targets. Biochemistry,2008, 47, 8253-8360.
13. Ewald, B.; Sampath, D.; Plunkett, W. Nucleoside analogs:molecular mechanisms signaling cell death. Oncogene, 2008, 27,6522-6537
14. Sampath, D.; Rao, V.A.; Plunkett, W. Mechanismsof apoptosis induction by nucleoside analogs. Oncogene, 2003, 2,9063-9074.
15. Jordheim, L.P.; Dumontet, C. Review of recent studies on resis-tance to cytotoxic deoxynucleoside analogues. Biochim. Biophys.Acta., 2007, 1776, 138-159.
16. Feld, J.J.; Hoofnagle, J.H. Mechanism of action of interferon andribavirin in treatment of hepatitis C. Nature, 2005, 436, 967-972.
17. Hofmann, W.P.; Herrmann, E.; Sarrazin, C.; Zeuzem, S. Ribavirinmode of action in chronic hepatitis C: from clinical use back to mo-lecular mechanisms. Liver Int., 2008, 28, 1332-1343.
18. Graci, J.D.; Cameron, C.E. Quasispecies, error catastrophe, andthe antiviral activity of ribavirin. Virology, 2002, 298, 175-180.
19. Crotty, S.; Maag, D.; Arnold, J.J.; Zhong, W.; Lau, J. Y. Hong, Z.;Andino, R., Cameron, C.E. The broad-spectrum antiviral ribonu-cleoside ribavirin is an RNA virus mutagen. Nat. Med., 2000, 6,1375-1379.
20. Gish, R.G. Treating HCV with ribavirin analogues and ribavirin-like molecules. J. Antimicrob. Chemother., 2006, 57, 8-13
21. Witkowski, J.T.; Robins, R.K.; Khare, G.P.; Sidwell, R.W.Synthesis and antiviral activity of 1,2,4-triazole-3-thiocarboxamideand 1,2,4-triazole-3-carboxamidine ribonucleosides. J. Med.Chem., 1973, 16, 935-937.
22. Kini, G.D.; Robins, R.K.; Avery,T.L. Synthesis and antitumor activity of ribavirin imidates. A newfacile synthesis of ribavirin amidine (1- -D-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride). J. Med. Chem., 1989, 32,1447-1449.
23. Gabrielsen, B.; Phelan, M.J.; Barthel-Rosa, L.; See, C.; Huggins, J.W.; Kefauver, D.F.; Monath, T.P.; Ussery, M.A.; Chmurny, G.N.; Schubert, E.M.; Upadhya, K.; Kwong, C.; Carter, D.A.; Secrist III, J.A.; Kirsi, J.J.; Shannon, W.M.; Sidwell, R.W.; Kini, G.D.; Robins, R.K. Synthesis and antiviral evaluation of N-carboxamidine-substituted analogues of l--D-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride. J. Med. Chem., 1992, 35,3231-3238.
24. Kumarapperuma, S.C.; Sun, Y.; Jeselnik, M.Chung, K. Parker, W.B. Jonsson, C.B. Arterburn, J.B. Structuraleffects on the phosphorylation of 3-substituted 1- -D-ribofuranosyl-1,2,4-triazoles by human adenosine kinase. Bioorg.Med. Chem. Lett., 2007, 17, 3203-3207.
25. Naik, S.R.; Witkowski, J.T.; Robins, R.K. Synthesis of nucleo-sides of 5-substituted-1,2,4-triazole-3-carboxamides. J. Heterocycl.Chem., 1974, 11, 57-61.
26. Witkowski, J.T.; Robins, R.K. Thechemical synthesis of the 1,2,4-triazole nucleosides related touridine, 2'-deoxyuridine, thymidine, and cytidine. J. Org. Chem.,1970, 35, 2635-2641.
27. Sanghvi, Y.S.; Hanna, N.B.; Larson, S.B. Fujitaki, J.M. Willis, R.C. Smith, R.A. Robins, R.K. Revankar,G.R. Synthesis and evaluation of 5-amino-1- -D-ribofuranosyl-1,2,4-triazole-3-carboxamidine and certain related nucleosides asinhibitors of purine nucleoside phosphorylase. J. Med. Chem.,1988, 31, 330-335.
28. Chung, D.-H.; Kumarapperuma, S.C.; Sun, Y.; Li, Q.; Chu, Y.-K.; Arterburn, J.B.; Parker, W.B. Smith, J. Spik, K. Ramanathan, H.N. Schmaljohn, C.S. Jonsson, C.B. Syn-thesis of 1--D-ribofuranosyl-3-ethynyl-[1,2,4]triazole and its in vi-tro and in vivo efficacy against Hantavirus. Antiviral Res., 2008,79, 19-27.
29. Poonian, M.S.; Nowoswiat, E.F. Novel precursor for the synthesisof C-nucleoside analogues. synthesis of the C-nucleoside analoguesof ribavirin, bredinin, and related compounds. J. Org. Chem., 1980,45, 203-208.
30. Fuertes, M.; Witkowski, J.T.; Streeter, D.G.; Robins, R.K. Syn-thesis and enzymatic activity of 1,2,4-triazole-3-carboxamide 6'-deoxyhomoribonucleoside-6'-phosphonic acid and related com-pounds. J. Med. Chem., 1974, 17, 642-645
31. Pickering, M.V. Witkowski, J.T. Robins, R.K. Synthesis of 1-(4-thio-beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide. J. Med. Chem., 1976,19, 841-842
32. Dudycz, L.; Shugar, D.; Clercq, E.D.; Descamps, J. Synthesis and determination of antiviral activity of the 2'(3')-O-methyl derivatives of ribavirin (1--D-ribofuranosyl-1,2,4-triazole-3-carboxamide). J. Med. Chem., 1977, 20, 1354-1356
33. Narang, A.S.; Vince, R. 1,2,4-Triazole amino nucleosides. 1--D-3'-Amino-3'-deoxyribofuranosyl-1,2,4-triazole-3-carboxamide and relatednucleosides. J. Med. Chem., 1977, 20, 1684-1687
34. Slater, M.J. Gowrie, C. Freeman, G.A. Short, S.A. Enzymatic synthesis andantiviral activity of 2'-deoxy-2'-fluoro-ribavirin. Bioorg. Med.Chem. Lett., 1996, 6, 2787-2790
35. Kini, G.D.; Henry, E.M.; Rob-ins, R.K.; Larson, S.B.; Marr, J.J.; Berens, R.L.; Bacchi, C.J.; Na-than, H.C.; Keithly, J.S. Synthesis, structure, and antiparasitic ac-tivity of sulfamoyl derivatives of ribavirin. J. Med. Chem., 1990,33, 44-48.
36. Witkowski, J.T.; Robins, R.K. Synthesis and chemistry of cer-tain azole nucleosides. In Chemistry and Biology of Nucleosidesand Nucleotides, Harmon, R.E.; Robins, R.K.; Townsend, L.B.Eds.; Academic Press, Inc. 1978, pp. 267-287.
37. Preobrazhen-skaya, M.N.; Korbukh, I.A. The synthesis and reactions of pyrrole,pyrazole, triazole, indole, indazole, and benzotriazole nucleosidesand nucleotides. In Chemistry of Nucleosides and Nucleostides,Townsend, L. B., Eds.; Plenum Press, New York, 1994, Volume 3,Chapter 1, pp. 47-97.
38. Miyasaka, T.; Tanaka, H.; Baba, M.; Hayakawa, H.; Walker, R.T.;Balzarini, J.; De Clercq, E. A novel lead for specific anti-HIV-1agents: 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J.Med. Chem., 1989, 32, 2507-2509.
39. Tanaka, H.; Baba, M.; Ubasawa, M.; Takashima, H. Sekiya, K.;Nitta, I.; Shigeta, S.; Walker, R.T.; De Clercq, E. Miyasaka, T. Synthesis and anti-HIV activity of 2-, 3-, and 4-substituted ana-logues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). J. Med. Chem., 1991, 34, 1394-1399.
40. Tanaka, H.; Baba, M. Saito, S. Miyasaka, T. Takashima, H. Sekiya, K. Ubasawa, M. Nitta, I. Walker, R. T. Nakashima, H. De Clercq, E. Specific anti-HIV-1 "acyclonucleosides" which cannot be phosphorylated: syn-thesis of some deoxy analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J. Med. Chem., 1991, 34, 1508-1511.
41. Esnouf, R.; Ren, J.S.; Ross, C.; Jones, Y.; Stammers, D.; Stuart, D. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nat. Struct. Biol., 1995, 2, 303-308.
42. Ren, J.S.; Esnouf, R.; Garman, E.; Somers, D.; Ross, C.; Kirby, L.;Keeling, J.; Darby, G.; Jones, Y.; Stuart, D.; Stammers, D. Highresolution structures of HIV-1RT from four RT-inhibitor com-plexes. Nat. Struct. Biol., 1995, 2, 293-302.
43. Hocek, M.; Hol, A.; Votruba, I.; Dvořáková, H. Synthesis andcytostatic activity of substituted 6-phenylpurine bases and nucleo-sides: application of the Suzuki-Miyaura cross-coupling reactionsof 6-chloropurine derivatives with phenylboronic acids. J. Med.Chem., 2000, 43, 1817-1825.
44. Hocek, M.; Nau, P.; Pohl, R.; Votruba, I.; Furman, P.A.; Thar-nish, P.M.; Otto, M.J. Cytostatic 6-arylpurine nucleosides. 6. SARin anti-HCV and cytostatic activity of extended series of 6-hetarylpurine ribonucleosides. J. Med. Chem., 2005, 48, 5869-5873.
45. Nau, P.; Pohl, R.; Votruba, I.; Džubák, P.; Hajdúch, M. Ameral, R. Birku, G. Wang, T. Ray, A.S. Mackman, R. Cihlar,T. Hocek, M. 6-(Het)aryl-7-Deazapurine Ribonucleosides asNovel Potent Cytostatic Agents. J. Med. Chem., 2010, 53, 460-470.
46. Loakes, D. The applications of universal DNA base analogues Nucleic Acids Res., 2001, 29, 2437-2447.
47. Wan, J.Q.; Zhu, R.Z.; Xia, Y.; Qu, F.Q.; Wu, Q.Y.; Yang, G.F. Neyts, J. Peng, L. Synthesis of 5-aryltriazole ribonucleosides viaSuzuki coupling and promoted by microwave irradiation. Tetrahe-dron Lett., 2006, 47, 6727-6731.
48. Zhu, R.Z.; Qu, F.Q.; Quéléver, G.; Peng, L. Direct synthesis of 5-aryltriazole acyclonucleosides via Suzuki coupling in aqueous solu-tion. Tetrahedron Lett., 2007, 48, 2389-2393.
49. Xia, Y.; Qu, F.Q.; Li, W.; Wu, Q.Y.; Peng, L. Synthesis of bitria-zolyl compounds via Huisgen reaction. Heterocycles, 2005, 65,345-352.
50. Xia, Y.; Fan, Z.J.; Yao, J.H.; Liao, Q.; Li, W.; Qu, F.Q.; Peng, L.Discovery of bitriazolyl compounds as novel antiviral candidatesfor combating the tobacco mosaic virus. Bioorg. Med. Chem. Lett.,2006, 16, 2693-2698.
51. Xia, Y.; Li, W.; Qu, F.Q.; Fan, Z.J.; Liu, X.F.; Berro, C.; Rauzy,E.; Peng, L. Synthesis of bitriazolyl nucleosides and unexpectedlydifferent reactivity of azidotriazole nucleoside isomers in the Huis-gen reaction. Org. Biomol. Chem., 2007, 5, 1695-1701.
52. Li, W.; Xia, Y.; Fan, Z.J.; Qu, F.Q.; Wu, Q.Y.; Peng, L. Bitriazolylacyclonucleosides with antiviral activity against tobacco mosaic virus. Tetrahedron Lett., 2008, 49, 2804-2809.
53. Zhu, R.Z.; Wang, M.H.; Xia, Y.; Qu, F.Q.; Neyts, J.; Peng, L.Arylethynyltriazole acyclonucleosides inhibit hepatitis C virus rep-lication. Bioorg. Med. Chem. Lett., 2008, 18, 3321-3327.
54. Wan, J.Q.; Xia, Y.; Liu, Y.; Wang, M.H.; Rocchi, P.; Yao, J.H. Qu, F.Q. Neyts, J. Iovanna, J.L. Peng, L. Discovery of novelarylethynyltriazole ribonucleosides with selective and effective an-tiviral and antiproliferative activity.J. Med. Chem., 2009, 52, 1144-1155.
55. Xia, Y.; Liu, Y.; Wan, J.Q.; Wang, M.H.; Rocchi, P.; Qu, F.Q. Iovanna, J.L. Peng, L. A novel triazole ribonucleoside down-regulates heat shock protein 27 and induces potent anticancer activ-ity on drug-resistant pancreatic cancer. J. Med. Chem., 2009, 52,6083-6096.
56. Li, W.; Fan, Y.T.; Xia, Y.; Rocchi, P.; Zhu, R.Z.; Qu, F.Q. Neyts, J. Iovanna, J.L. Peng, L. Cu-mediated selective N-arylationof aminotriazole acyclonucleosides. Helv. Chim. Acta, 2009, 92,1503-1513.
57. Liu, Y.; Xia, Y.; Fan, Y.T.; Maggiani, A.; Rocchi, P. Qu, F.Q. Iovanna, J.L.; Peng, L. N-Aryltriazole ribonucleosideswith potent antiproliferative activity against drug-resistant pancrea-tic cancer. Bioorg. Med. Chem. Lett., 2010, 20, 2503-2507.
58. Xia, Y.; Wan, J.Q.; Qu, F.Q.; Peng, L. Synthesis of nucleosideanalogues with aromatic systems appended on the triazole nucleo-side. Collection Symposium Series. Hocek, M. Ed. Institute of Or-ganic Chemistry and Biochemistry, Academy of Sciences of theCzech Republic, Prague 2008, vol. 10, p. 224.
59. Wu, Q.Y.; Qu, F.Q.; Wan, J.Q.; Zhu, X.; Xia, Y.; Peng, L. Design,synthesis, and characterization of photolabeling probes for thestudy of the mechanisms of the antiviral effects of ribavirin. Helv.Chim. Acta, 2004, 87, 811-819.
60. Wu, Q.Y.; Qu, F.Q.; Wan, J.Q.; Xia, Y.; Peng, L. Photolabelingprobes of ribavirin and EICAR. Nucleosides, Nucleotides NucleicAcids, 2005, 999-1008.
61. Stanforth, S.P. Catalytic cross-coupling reactions in biaryl synthe-sis. Tetrahedron, 1998, 54, 263-303.
62. Evano, G.; Blanchard, N.; Toumi, M. Copper-mediated couplingreactions and their applications in natural products and designedbiomolecules synthesis. Chem. Rev., 2008, 108, 3054-3131.
63. Kappe, C.O. Controlled microwave heating in modern organicsynthesis. Angew Chem. Int. Ed. Engl., 2004, 43, 6250-6284.
64. Prusiner, P.; Sundaralingam, M. A new class of synthetic nucleo-side analogues with broad-spectrum antiviral properties. Nat. NewBiol., 1973, 244, 116-118.
65. Insight: Hepatitis C. Nature, 2005, 436, 929-978.
66. Lavanchy, D. The global burden of hepatitis C. Liver Int., 2009, 29(Suppl 1),74-81.
67. De Francesco, R.; Migliaccio, G. Challenges and successes indeveloping new therapies for hepatitis C. Nature 2005, 436, 953-960.
68. Webster, D.P.; Klenerman, P.; Collier, J.; Jeffery, K.J. De-velopment of novel treatments for hepatitis C. Lancet Infect. Dis.,2009, 9, 108-117.
69. Gordon, C. P.; Keller, P. A. Control of hepa-titis C: A medicinal chemistry perspective. J. Med. Chem., 2005,48, 1-20.
70. Peng, L.; Qu, F.Q.; Zhu, R.Z.; Neyts, J. Triazole derivatives asviral replication inhibitors. Patent GB0714649.1, 2007, PatentPCT/BE2008/000059, 2008.
71. Liao, Q.; Yao, J.H.; Yuan, S.G. Prediction of mutagenic toxicity bycombination of recursive partitioning and support vector machines. Mol. Divers., 2007, 11, 59-72.
72. Liao, Q.; Yao, J.H.; Li, F.; Yuan, S.G.; Doucet, J.P.; Panaye, A. Fan, B.T. CISOC-PSCT: A predictive system for carcinogenic toxicity. SAR QSAR Environ. Res., 2004, 15, 217-235.
73. Liu, Y.; Xia, Y.; Li, W.; Cong, M.; Maggiani, A.; Leyssen, P.; Qu, F.Q.; Neyts, J.; Peng, L. S-aryltriazole acyclonucleosides: synthesisand biological evaluation against hepatitis C virus. Bioorg. Med.Chem. Lett., 2010, 20, Doi: 10.1016/j.bmcl.2010.04.115.
74. Scholthof, K.B. Tobacco mosaic virus: a model system for plantbiology. Annu. Rev. Phytopathol., 2004, 42, 13-34.
75. Qu, F.Q.; Xia, Y.; Fan, Z.J.; Li, W.; Peng, L. The synthesis andapplications of the bitriazolyl compounds. Patent CN 100334084C,2005.
76. Li, D.; Xie, K.; Wolff, R.; Abbruzzese, J.L. Pancreatic cancer. TheLancet, 2004, 363, 1049-1057.
77. Pierantoni, C.; Pagliacci, A.; Scartozzi, M.; Berardi, R.; Bian-coni, M.; Cascinu, S. Pancreatic cancer: progress in cancer therapy. Crit. Rev. Oncol. Hematol., 2008, 67, 27-38.
78. Wong, H.H. Lemoine, N.R. Pancreatic cancer: molecular pathogenesis and newtherapeutic targets. Nat. Rev. Gastroenterol. Hepatol., 2009, 6,412-422.
79. Mini, E.; Nobili, S.; Caciagli, B.; Landini, I.; Mazzei, T. Cellularpharmacology of gemcitabine. Ann. Oncol., 2006, 17(Suppl 5), v7-v12.
80. Rivera, F.; López-Tarruella, S.; Vega-Villegas, M.E.; Salcedo, M. Treatment of advanced pancreatic cancer: from gemcitabine singleagent to combinations and targeted therapy. Cancer Treat. Rev.,2009, 35, 335-339.
81. Peng, L.; Xia, Y.; Wan, J.Q.; Rocchi, P.; Liu, Y.; Wang, M.H.; Qu, F.Q.; Iovana, J.L. Novel triazole nucleoside derivatives, theirpreparation and their application in therapeutics. Patent EU 08155481.8, 2008. PCT/EP2009/055213, 2009.
82. Huang, P.; Chubb, S.; Hertel, L.W.; Grindey, G.B.; Plunkett, W.Action of 2', 2'-difluorodeoxycytidine on DNA synthesis. CancerRes., 1991, 51, 6110-6117.
83. Arrigo, A.-P.; Simon, S.; Gibert, B.; Kretz-Remy, C.; Nivon, M.; Czekalla, A.; Guillet, D.; Moulin, M.; Diaz-Latoud, C.; Vicart, P. Hsp27 (HspB1) and alpha-B-crystallin (HspB5) as therapeutictargets, FEBS Lett., 2007, 581, 3665-3674.
84. Concannon, C. G.;Gorman, A. M.; Samali, A. On the role of Hsp27 in regulatingapoptosis. Apoptosis, 2003, 8, 61-70.
85. Mori-Iwamoto, S.; Kuramitsu, Y.; Ryozawa, S.; Mikuria, K. Fujimoto, M. Maehara, S.-I. Maehara, Y. Okita, K. Nakamura, K. Sakaida, I. Proteomics finding heat shock protein 27 as a bio-marker for resistance of pancreatic cancer cells to gemcitabine. Int.J. Oncol., 2007, 31, 1345-1350.
86. Mori-Iwamoto, S.; Taba, K. Kuramitsu, Y. Ryozawa, S. Tanaka, T. Maehara, S.-I Maehara, Y.; Okita, K.; Nakamura, K.; Sakaida, I. Interferon- down-regulates heat shock protein 27 of pancreatic cancer cells and helpsin the cytotoxic effect of gemcitabine. Pancreas, 2009, 38, 224-226.
87. Rocchi, P.; So, A.; Kojima, S.; Signaevsky, M.; Beraldi, E. Fazli, L.; Hurtado-coll, A. Yamanaka, K. Gleave, M. Heat shockprotein 27 increases after androgen ablation and plays a cytoprotec-tive role in hormone-refractory prostate cancer. Cancer Res., 2004,64, 6595-6602.
88. Rocchi, P.; Beraldi, E.; Ettinger, S.; Fazli, L. Vessella, R.L. Nelson, C. Gleave, M. Increased Hsp27 after an-drogen ablation facilitates androgen-independent progression inprostate cancer via signal transducers and activators of transcription3-mediated suppression of apoptosis. Cancer Res., 2005, 65,11083-11093.
89. Hotte, S.J.; Yu, E.Y.; Hirte, H.W.; Higano, C.S. Gleave, M. Chi, K.N. OGX-427, a 2'-methoxyethyl antisense oli-gonucleotide (ASO), against Hsp27: Results of a first-in-humantrial. J. Clin. Oncol., 2009, 27:15s (suppl; abstr 3506).