Molecular modeling, synthesis, and preliminary biological evaluation of glutathione-S-transferase inhibitors as potential therapeutic agents

Journal of Medicinal Chemistry

Volumn 48, Issue 19, 2005, Pages 6084-6089

  Procopio, Antonio ^a   Alcaro, Stefano ^a   Cundari, Sante ^c   De Nino, Antonio ^c   Ortuso, Francesco ^b   Sacchetta, Paolo ^d   Pennelli, Alfonso ^d   Sindona, Giovanni ^c  

^a UNIVERSITY MAGNA GRAECIA OF CATANZARO   (Italy)

^b UNIVERSITY OF CALABRIA   (Italy)

^c Sigma Tau SpA   (Italy)

^d UNIVERSITY OF CHIETI   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ALKYLATING AGENT; ENZYME INHIBITOR; ETHYLENE OXIDE DERIVATIVE; GLUTATHIONE; GLUTATHIONE TRANSFERASE; GLUTATHIONE TRANSFERASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DIASTEREOISOMER; DRUG CONFORMATION; DRUG CONJUGATION; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME KINETICS; HUMAN; HYDROGEN BOND; IN VITRO STUDY; MASS SPECTROMETRY; MOLECULAR MODEL; MONTE CARLO METHOD; PROTON NUCLEAR MAGNETIC RESONANCE; REVERSED PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; SPECTROPHOTOMETRY;

CATALYTIC DOMAIN; ETHYLENE OXIDE; GLUTATHIONE; GLUTATHIONE TRANSFERASE; HUMANS; MODELS, MOLECULAR; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 24944544704     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0504609     Document Type: Article

References (69)

1. (a) Scheeter, R. L.; Alaoui-Jamali, M. A.; Woo, A.; Fahl, W. E.; Batist, G. Expression of a Rat Glutathione S-transferase Complementary DNA in Rat Mammary Carcinoma Cells: Impact upon Alkylator-induced Toxicity. Cancer Res. 1993, 53, 4900-4906.
2. (b) Dirven, H. A. A. M.; van Ommen, B.; van Bladeren, P. J. Glutathione Conjugation of Alkylating Cytostatic Drugs with Nitrogen Mustard Group and Role of Glutathione S-Transferases. Chem. Res. Toxicol. 1996, 9, 351-360.
3. (c) Ouar, Z.; Lacave, R.; Bens, M.; Vandewalle, A. Mechanisms of altered sequestration and efflux of chemotherapy drugs by multidrug-resistant cells. Cell Biol. Toxicol. 1999, 15, 91-100.
4. (a) Leyland-Jones, B. R.; Townsend, A. J.; Tu, C. P.; Cowan, K. H.; Goldsmith, M. E. Antineoplastic drug sensitivity of human MCF-7 breast cancer cells stably transfected with a human alpha class glutathione S-transferase gene. Cancer Res. 1991, 15, 587-594.
5. (b) Calvert, P.; Yao, K. S.; Hamilton, T. C.; O'Dwyer, P. J. Clinical studies of reversal of drug resistance based on glutathione. Chem. Biol. Interact. 1998, 111-112, 213-224.
6. (a) Batist, G.; Behrens, B. C., Makuch, R., Hamilton, T. C.; Katki, A. G.; Louie, K. G.; Myers, C. E.; Ozols, R. F. Serial determinations of glutathione levels and glutathione-related enzyme activities in human tumor cells in vitro. Biochem. Pharmacol. 1986, 35, 2257-2259.
7. (b) Meister, A.; Anderson, M. E. Glutathione. Annu. Rev. Biochem. 1983, 52, 711-760.
8. (a) Armstrong, R. N. Structure, Catalytic Mechanism and Evolution of the Glutathione Transferases. Chem. Res. Toxicol. 1997, 10, 2-18.
9. (b) Armstrong, R. N. Glutathione S-transferases: reaction mechanism, structure, and function. Chem. Res. Toxicol. 1991, 4, 131-140.
10. Hayes, J. D., Flanagan, J. U., Jowsey, I. R. Glutathione Transferases. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 51-88.
11. (a) Waxman, D. J. Glutathione S-Transferases: Role in Alkylating Agents Resistance and Possible Target For Modulation Chemotherapy-A Review. Cancer Res. 1990, 50, 6449-6454.
12. (b) Coles, B.; Ketterer, B. The role of glutathione and glutathione transferases in chemical carcinogenesis. Crit. Rev. Biochem. Mol. Biol. 1990, 25, 47-70.
13. (c) Townsend, D. M.; Tew, K. D. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene 2003, 22, 7369-7375.
14. (a) Green, J. A.; Vistica, D. T.; Young, R. C.; Hamilton, T. C.; Rogan, A. M.; Ozols, R. F. Potentiation of melphalan cytotoxicity in human ovarian cancer cell lines by glutathione depletion. Cancer Res. 1984, 44, 5427-5431.
15. (b) Hamilton, T. C.; Winker, M. A.; Louie, K. G.; Batist, G.; Behrens, B. C.; Tsuruo, T., Grotzinger, K. R.; McKoy, W. M.; Young, R. C.; Ozols, R. F. Augmentation of adriamycin, melphalan, and cisplatin cytotoxicity in drug-resistant and -sensitive human ovarian carcinoma cell lines by buthionine sulfoximine mediated glutathione depletion. Biochem. Pharmacol. 1985, 34, 2583-2586.
16. (c) Hall, A.; Robson, C. N.; Hickson, I. D.; Harris, A. L.; Proctor, S. J.; Cattan, A. R. Possible role of inhibition of glutathione S-transferase in the partial reversal of chlorambucil resistance by indomethacin in a Chinese hamster ovary cell line. Cancer Res. 1989, 49, 6265-6228.
17. (d) Gupta, V.; Jani, J. P.; Jacobs, S.; Levitt, M.; Fields, L.; Awasthi, S.; Xu, B. H.; Sreevardhan, M.; Awasthi, Y. C.; Singh, S. V. Activity of melphalan in combination with the glutathione transferase inhibitor sulfasalazine. Cancer Chemother Pharmacol. 1995, 36, 13-19.
18. (e) Awasthi, S.; Sharma, R.; Singhai, S. S.; Herzog, N. K.; Chaubey, M.; Awasthi, Y. C. Modulation of cisplatin cytotoxicity by sulphasalazine. Br. J. Cancer 1994, 70, 190-194.
19. (a) Di Ilio, C.; Del Boccio, G.; Aceto, A.; Casaccia, R.; Mucilli, F.; Federici, G. Elevation of glutathione transferase activity in human lung tumor. Carcinogenesis 1988, 9, 335-340.
20. (b) Howie, A. F.; Forrester, L. M.; Glancey, M. J.; Schlager, J. J.; Powis, G.; Hayer, J. D.; Wolf, C. R.; Glutathione S-transferase and glutathione peroxidase expression in normal and tumor tissues. Carcinogenesis 1990, 11, 451-458.
21. (c) Eimoto, H.; Tsutsumi, M.; Nakajima, A.; Yamamoto, K.; Takashima, Y.; Maruyama, H.; Konishi, J. Expression of the glutathione S-transferase placental form in human lung carcinomas. Carcinogenesis 1988, 9, 2325-2327.
22. (a) Ranganathan, S.; Tew, K. D. Immunohistochemical localization of glutathione S-transferase α, μ, and π in normal and in tumor tissue from human colon. Carcinogenesis 1991, 12, 2383-2387.
23. (b) Di Ilio, C.; Del Boccio, Federici, G. Alteration of glutathione transferase isoenzymeconcentration in human renal carcinomas. Carcinogenesis 1987, 8, 861864.
24. (a) Harrison, D. J.; Kharbanda, R.; Bishop, D.; McLellan, L. I.; Hayes, J. D. Glutathione S-transferase isoenzymes in human renal carcinoma demonstrated by immunohistochemistry. Carcinogenesis 1989, 10, 1257-1260.
25. (b) Shiratori, Y.; Soma, Y.; Maruyama, H.; Sato, S.; Takano, A.; Sato, K. Immunohistochemical detection of the placental form of glutathione S-transferase in dysplastic and neoplastic human uterine cervix lesions. Cancer Res. 1987, 47, 6806-6809.
26. Mosow, J. A.; Fairchild, R. R.; Madden, M. J.; Ranson, D. T.; Wieand, H. S.; O'Brien, E. E.; Poplack, D. J.; Cossman, J.; Myers, C. E.; Cowan, K. H. Expression of anionic glutathione S-transferase and P-glycoprotein genes in human tissues and tumors. Cancer Res. 1989, 49, 1422-1428.
27. Hayes, J. D.; Pulford, D. J. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isozymes to cancer chemoprotection and drug resistance. Crit. Rev. Biochem. Mol. Biol. 1995, 30, 445-600.
28. (a) Reinemer, P.; Dirr, H. W.; Ladenstein, R.; Schäffer, J.; Gallay, O.; Huber, R. The three-dimensional structure of class π glutathione S-transferase in complex with glutathione sulfonate at 2.3 Å resolution. EMBO J. 1991, 10, 1997-2005.
29. (b) Dirr, H. W.; Mann, K.; Huber, R.; Ladenstein, R.; Reinemer, P. Class pi glutathione S-transferase from pig lung. Purification, biochemical characterization, primary structure and crystallization. Eur J Biochem. 1991, 196, 693-698.
30. (c) Kauvar S. H.; Tew K. D. Importance of glutathione and associated enzymes in drug response. Oncol. Res. 1997, 9, 295-302.
31. (a) Lyttle, M. H.; Hocker, M. D.; Hui, H. C.; Caldwell, C. G.; Aaron, D. T.; Engqvist-Goldstein, A.; Flatgaard, J. E.; Bauer, K. E. Isozyme-specific glutathione-S-transferase inhibitors: design and synthesis. J. Med. Chem. 1994, 37, 189-194.
32. (b) Satyam, A.; Hocker, M. D.; Kane-Maguire, K. A.; Morgan, A. S.; Villar, H. O.; Lyttle, M. H. Design, synthesis, and evaluation of latent alkylating agents activated by glutathione S-transferase. J. Med. Chem. 1996, 39, 1736-1747.
33. (c) Ciaccio, P. J.; Shen, H.; Kruh, G. D.; Tew, K. D. Effects of Chronic Ethacrynic Acid Exposure on Glutathione Conjugation and MRP Expression in Human Colon Tumor Cells. Biochem. Biophys. Res. Commun. 1996, 222, 111-115.
34. (d) Townsend D. M.; Tew, K. D. The role of glutathione S-transferase in anti-cancer drug resistance Oncogene 2003, 22, 7369-7375.
35. (e) Laidler, K. J. A Glossary of Terms used in Chemical Kinetics Including Reaction Dynamics. Pure Appl. Chem. 1996, 68, 149-192.
36. (a) Clapper, M. L.; Hoffman, S. J.; Tew, K. D. Glutathione S-transferases in normal and malignant human colon tissue. Biochim Biophys Acta 1991, 1096, 209-216.
37. (b) Oakley, A. J.; Lo Bello, M.; Mazzetti, A. P.; Federici, G.; Parker, M. W. The glutathione conjugate of ethacrynic acid can bind to human pi class glutathione transferase P1-1 in two different modes. FEBS Lett. 1997, 419, 32-36.
38. (c) Mulder, T. P.; Peters, W. H.; Wobbes, T.; Witteman, B. J.; Jansen, J. B. Measurement of glutathione S-transferase P1-1 in plasma: pitfalls and significance of screening and follow-up of patients with gastrointestinal carcinoma. Cancer 1997, 80, 873-880.
39. (a) Schultz, M.; Dutta, S.; Tew, K. D. Inhibitors of glutathione S-transferases as therapeutic agents. Adv. Drug Delivery Rev. 1997, 26, 91-104.
40. (b) O'Brien, M. L.; Tew, K. D. Glutathione and related enzymes in multidrug resistance. Eur. J. Cancer Part A 1996, 32, 967-978.
41. Adang, A. E.; Brussee, J.; van der Gen, A.; Mulder, G. J. The glutathione-binding site in glutathione-S-transferases. Investigation of the cysteinyl, glycyl and gamma-glutamyl domains. Biochem J. 1990, 269, 47-54.
42. Flatgaard, J. E. F.; Bauer, K. E.; Kauvar, L. M. Isozyme specificity of novel glutathione-S-transferase inhibitors. Cancer Chemother. Pharmacol. 1993, 33, 63-70.
43. (a) Morgan, A. S.; Ciaccio, P. J.; Tew, K. D.; Kawar, L. M. Isozyme-specific, glutathione-S-transferase inhibitors potentiate drug sensitivity in cultured human cell lines. Cancer Chemother. Pharmacol. 1996, 37, 363-370.
44. (b) Ciaccio, P. J.; Shen, H.; Jaiswal, A. K.; Lyttle, M. H.; Tew, K. D. Modulation of detoxification gene expression in colon HT29 cells by glutathione-S-transferase inhibitors. Mol. Pharmacol. 1995, 48, 639-647.
45. (a) Ji, X.; Johnson, W. W.; Sesay, M. A.; Dickert, L.; Prasad, S. M.; Ammon, H. L.; Armstrong, R. N.; Gilliland, G. L. Structure and function of the xenobiotic substrate binding site of a glutathione S-transferase as revealed by X-ray crystallographic analysis of product complexes with the diastereomers of 9-(S-glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene. Biochemistry 1994 33, 1043-1052.
46. (b) Zhang, X. X.; Chakrabarti, S.; Malick, M. A.; Richer, C. L. Cytogenotoxicity of N-acetyl-S-(1/2-phenyl-2-hydroxyethyl)-cysteine (NAPEC) in cultured human blood lymphocytes. Cytogenotoxicity of N-acetyl-S-(1/2-phenyl-2- hydroxyethyl)-cysteine (NAPEC) in cultured human blood lymphocytes. Mutat. Res. 1993, 319, 121-127.
47. (a) Kitahara, A.; Yamazaki, T.; Ishikawa, T.; Camba, E. A.; Sato, K. Changes in activities of glutathione peroxidase and glutathione reductase during chemical hepatocarcinogenesis in the rat. Gann 1983, 74, 649-655.
48. (b) Kitahara, A.; Satoh, K.; Nishimura, K.; Ishikawa, T.; Ruike, K.; Sato, K.; Tsuda, H.; Ito, N. Changes in molecular forms of rat hepatic glutathione S-transferase during chemical hepatocarcinogenesis. Cancer Res. 1984, 44, 2698-2703.
49. (c) Henderson, C. J.; McLaren, A. W.; Moffat, G. J.; Bacon, E. J.; Wolf, C. R. Pi-class glutathione S-transferase: regulation and function. Chemico-Biol. Interact. 1998, 111-112, 69-82.
50. (d) Henderson, C. J.; Smith, A. G.; Ure, J.; Brown, K.; Bacon, E. J.; Wolf, C. R. Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases. Proc. Natl. Acad. Sci. U S A. 1998, 95, 5275-5280.
51. (e) Jernström, B.; Dock, L.; Hall, M.; Mannervik, B.; Tahir, M. K.; Grover, P. L. Glutathione transferase catalyzed conjugation of benzo[a]pyrene 7,8-diol 9, 10-epoxide with glutathione in human skin. Chemico-Biol. Interact. 1989, 70, 173-180.
52. (a) PDB: Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank. Nucleic Acids Res. 2000, 28, 235-242
53. (b) See Supporting Information for a complete code list of the 45 GST human isoform models found into the PDB.
54. Oakley, A. J.; Lo Bello, M.; Battistoni, A.; Ricci, G.; Rossjohn, J.; Villar, H. O.; Parker, M. W. The structures of human glutathione transferase P1-1 in complex with glutathione and various inhibitors at high resolution. J Mol Biol. 1997, 274, 84-100
55. Goodford, P. J. A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules. J. Med. Chem. 1985, 28, 849-857.
56. (a) Weiner, S. J.; Kollman, P. A.; Case, D. A.; Singh, U. C.; Chio, C.; Alagona, G.; Profeta, S.; Weiner, P. A New Force Field for Molecular Mechanical Simulation of Nucleic Acids and Proteins. J. Am. Chem. Soc. 1984, 106, 765-784.
57. (b) Weiner, S. J.; Kollman, P. A.; Case, D. A. An All-Atom Force Field for Simulations of Proteins and Nucleic Acids. J. Comput. Chem. 1986, 7, 230-252.
58. Hasel, W.; Hendrickson, T. F.; Still, W. C., A Rapid Approximation to the Solvent Accessible Surface Areas of Atoms. Tetrahedron Comput. Methodol. 1988, 1, 103-116.
59. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C., MacroModel-An Integrated Software System for Modeling Organic and Bioorganic Molecules using Molecular Mechanics. J. Comput. Chem. 1990, 11, 440-467.
60. (a) Alcaro, S.; Arena, A.; Neri, S.; Ottana, R.; Ortuso, F.; Pavone, B.; Vigorita, M. G. Design and synthesis of DNA-intercalating 9-fluoren-â-O- glycosides as potential IFN-inducers, and antiviral and cytostatic agents. Bioorg., Med. Chem. 2004, 12, 1781-1791.
61. (b) Alcaro, S.; Arena, A.; Di Bella, R.; Neri, S.; Ottanà, R.; Ortuso, F.; Pavone, B.; Vigorita, M. G. 9-Fluorenon-4-carboxamides: synthesis, conformational analysis, anti-HSV-2, and immunomodulatory evaluation. Note II. ARKIVOC 2004, (v) 334-348.
62. Alcaro, S.; Arena, A.; Di Bella, R.; Neri, S.; Ottanà, R.; Ortuso, F.; Pavone, B.; Trincone, A.; Vigorita, M. G. Biocatalysed synthesis of β-O-glucosides from 9-fluorenon-2-carbohydroxyesters. Part 3: IFN-inducing and anti-HSV-2 properties. Bioorg., Med. Chem. 2005, 13, 3371-3378.
63. Alcaro, S.; Gasparrini, F.; Incani, O.; Mecucci, S.; Misiti, D.; Pierini, M.; Villani, C. A Quasi-Flexible Automatic Docking Processing for Studying Stereoselective Recognition Mechanisms. Part I. Protocol Validation. J. Comput. Chem. 2000, 21, 515-530.
64. Before the RMSd comparison the crystallographic model was submitted to a constrained energy minimisation in the same of 1-4 GST starting geometries.
65. Cundari, S.; Dalpozzo, R.; De Nino, A.; Procopio, A.; Sindona, G.; Athanassopulos, K. A Facile One-Pot Synthesis of Very Useful Building Blocks N-Boc-S-alkylated cysteines. Tetrahedron 1999, 55, 10155-10162.
66. (a) Chen, S. T.; Wang, K. T. Phase-transfer reagents as C-terminal protecting groups; facile incorporation of free amino acids or peptides into peptide sequences. J. Chem. Soc., Chem. Commun. 1990, 1045-1047.
67. (b) Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A.; Shah, R. D.; Villani, F. J.; Zhang, F. Hydrolysis of Polipeptide Esters with Tetrabutylammonium Hydroxide. Tetrahedron Lett. 1998, 39, 3391-3394.
68. Wang, M. L.; Yang, C. Y. Reaction Mechanism of Phase-Transfer catalysis Initiated by Hydroxide Ion: Effect of Alkalinity. Tetrahedron 1999, 55, 6275-6288.
69. Habig, W. H. and Jakoby, W. B. Glutathione S-transferases (rat and human). Methods Enzymol. 1981, 77, 398-405.