Synthesis and Evaluation of Nitroheterocyclic Carbamate Prodrugs for Use with Nitroreductase-Mediated Gene-Directed Enzyme Prodrug Therapy

Journal of Medicinal Chemistry

Volumn 46, Issue 25, 2003, Pages 5533-5545

  Hay, Michael P ^a   Anderson, Robert F ^a   Ferry, Dianne M ^a   Wilson, William R ^a   Denny, William A ^a  

^a UNIVERSITY OF AUCKLAND   (New Zealand)

Author keywords

[No Author keywords available]

Indexed keywords

1 METHYL 2 NITRO 1H IMIDAZOL 5 YLMETHYLCARBAMATE; 1 METHYL 5 NITRO 1H IMIDAZOL 2 YLMETHYLCARBAMATE; 5 (1 AZIRIDINYL) 2,4 DINITROBENZAMIDE; ANTINEOPLASTIC AGENT; BROMINE DERIVATIVE; CARBAMIC ACID DERIVATIVE; HETEROCYCLIC COMPOUND; NITROREDUCTASE; PHENYLENEDIAMINE MUSTARD; PRODRUG; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL KILLING; CELL LINE; CHO CELL; CONTROLLED STUDY; DRUG CYTOTOXICITY; DRUG EFFICACY; DRUG METABOLISM; DRUG POTENCY; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; ELECTRON; GENE DIRECTED ENZYME PRODRUG THERAPY; GENE THERAPY; HUMAN; HUMAN CELL; IC 50; MALE; MOUSE; NONHUMAN; REACTION ANALYSIS; REDUCTION; SOLID TUMOR; STRUCTURE ANALYSIS;

ANIMALS; ANTINEOPLASTIC AGENTS, ALKYLATING; CARBAMATES; CELL LINE, TUMOR; CRICETINAE; DRUG STABILITY; ESCHERICHIA COLI; GENE THERAPY; GENE TRANSFER TECHNIQUES; HUMANS; INDOLES; MALE; MICE; MICE, INBRED C3H; MICE, NUDE; NITROGEN MUSTARD COMPOUNDS; NITROREDUCTASES; OXIDATION-REDUCTION; PRODRUGS; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSFECTION; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 0344118703     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm030308b     Document Type: Article

References (56)

1. Huber, B. E.; Richards, C. A.; Austin, E. A. VDEPT: An enzyme/prodrug gene therapy approach for the treatment of metastatic colorectal cancer. Adv. Drug Deliv. Rev. 1995, 17, 279-292.
2. Martin, L.-A.; Lemoine, N. R. Direct cell killing by suicide genes. Cancer Metastasis Rev. 1996, 15, 301-316.
3. Niculaescu-Duvaz, I.; Spooner, R.; Marais, R.; Springer, C. J. Gene-directed enzyme prodrug therapy. Bioconjugate Chem. 1998, 9, 4-22.
4. Anlezark, G. M.; Melton, R. G.; Sherwood, R. F.; Coles, B.; Friedlos, F. ; Knox, R. J. The bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954)-I. Purification and properties of a nitroreductase enzyme from Escherichia coli-A potential enzyme for antibody-directed enzyme prodrug therapy (ADEPT). Biochem. Pharmacol. 1992, 44, 2289-2296.
5. Knox, R. J.; Friedlos, F.; Sherwood, R. F.; Melton, R. G.; Anlezark, G. M. The bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954)-II. A comparison of an Escherichia coli nitroreductase and Walker DT diaphorase. Biochem. Pharmacol. 1992, 44, 2297-2301.
6. Michael, N. P.; Brehm, J. K.; Anlezark, G. M.; Minton, N. P. Physical characterisation of the Escherichia coli B gene encoding nitroreductase and its overexpression in Escherichia coli K12. FEMS Microbiol. Lett. 1994, 124, 195-202.
7. Skelly, J. V.; Collins, P. J.; Knox, R. J.; Anlezark, G. M.; Melton, R. G. Crystallization and preliminary crystallographic data for an FMN-dependent nitroreductase from Escherichia coli B. J. Mol. Biol. 1994, 238, 852-853.
8. Djeha, A. H.; Hulme, A.; Dexter, M. T.; Mountain, A.; Young, L. S.; Searle, P. F.; Kerr, D. J.; Wrighton, C. J. Expression of Escherichia coli B nitroreductase in established human tumor xenografts in mice results in potent antitumoral and bystander effects upon systemic administration of the prodrug CB1954. Cancer Gene Ther. 2000, 7, 721-731.
9. Djeha, A. H.; Thomson, T. A.; Leung, H.; Searle, P. F.; Young, L. S.; Kerr, D. J.; Harris, P. A.; Mountain, A.; Wrighton, C. J. Combined adenovirus-mediated nitroreductase gene delivery and CB1954 treatment: A well-tolerated therapy for established solid tumors. Mol. Ther. 2001, 3, 233-240.
10. Chung-Faye, G.; Palmer, C.; Anderson, D.; Clark, J.; Downes, M.; Baddeley, J.; Hussain, S.; Murray, P. I.; Searle, P.; Seymour, L.; Harris, P. A.; Ferry, D.; Kerr D. J. Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: A phase I and pharmacokinetic study of its prodrug, CB 1954. Clin. Cancer Res. 2001, 7, 2662-2668.
11. Palmer, D. H.; Mautner, V.; Mirza, D.; Buckels, J.; Olliff, D.; Hull, D. ; Mountain, A.; Harris, P.; Djeha, H.; Ellis, J.; Horne, M.; Hill, S.; Wrighton, C.; Searle, P. F.; Kerr, D. J.; Young, L. S.; James, N. D. Virus-directed enzyme prodrug therapy (VDEPT): Clinical trials with adenoviral nitroimidazole reductase (Ad-ntr). Brit. J. Cancer 2002, 86 (Suppl 1), S30.
12. Anlezark, G. M.; Melton, R. G.; Sherwood, R. F.; Wilson, W. R.; Denny, W. A.; Palmer, B. D.; Friedlos, F.; Williams, A. Bioactivation of dinitrobenzamide mustards by an E. coli B nitroreductase. Biochem. Pharmacol. 1995, 50, 609-618.
13. Atwell, G. J.; Boyd, M.; Palmer, B. D.; Anderson, R. F.; Pullen, S. M.; Wilson, W. R.; Denny, W. A. Synthesis and evaluation of 4-substituted analogues of 5-[N,N-bis-(2-chloroethyl)amino]-2-nitrobenzamide as bioreductively activated prodrugs using an Escherichia coli nitroreductase. Anti-Cancer Drug Design 1996, 11, 553-567.
14. Friedlos, F.; Denny, W. A.; Palmer, B. P.; Springer, C. J. Mustard prodrugs for activation by Escherichia coli nitroreductase in gene-directed enzyme prodrug therapy. J. Med. Chem. 1997, 40, 1270-1275.
15. Wilson, W. R.; Pullen, S. M.; Hogg, A.; Helsby, N. A.; Hicks, K. O.; Denny, W. A. Quantitation of bystander effects in nitroreductase suicide gene therapy using three-dimensional cell cultures. Cancer Res. 2002, 62, 1425-1432.
16. Mauger, A. B.; Burke, P. J.; Somani, H. H.; Friedlos, F.; Knox, R. J. Self-immolative prodrugs: Candidates for antibody-directed enzyme prodrug therapy in conjunction with a nitroreductase enzyme. J. Med. Chem. 1994, 37, 3452-3458.
17. Hay, M. P.; Wilson, W. R.; Denny, W. A. A novel enediyne prodrug for antibody-directed enzyme prodrug therapy (ADEPT) using E. coli B nitroreductase. Bioorg. Med. Chem. Lett. 1995, 5, 2829-2834.
18. Hay, M. P.; Wilson, W. R.; Denny, W. A. Nitrobenzyl carbamate prodrugs of enediynes for nitroreductase gene-directed enzyme prodrug therapy (GDEPT). Bioorg. Med. Chem. Lett. 1999, 9, 3417-3422.
19. Tercel, M.; Denny, W. A.; Wilson, W. R. A novel nitro-substituted seco-CI: Application as a reductively activated ADEPT prodrug. Bioorg. Med. Chem. Lett. 1996, 6, 2741-2744.
20. Sagnou, M. J.; Howard, P. W.; Gregson, S. J.; Eno-Amooquaye, E.; Burke, P. J.; Thurston, D. E. Design and synthesis of novel pyrrolobenzodiazepine (PBD) prodrugs for ADEPT and GDEPT. Bioorg. Med. Chem. Lett. 2000, 10, 2083-2086.
21. Lee, M.; Simpson, J. E., Jr.; Woo, S.; Kaenzig, C.; Anlezark, G. M.; Eno-Amooquaye, E.; Burke, P. J. Synthesis of an aminopropyl analogue of the experimental anticancer drug tallimustine, and activation of its 4-nitrobenzylcarbamoyl prodrug by nitroreductase and NADH. Bioorg. Med. Chem. Lett. 1997, 7, 1065-1070.
22. Hay, M. P.; Atwell, G. J.; Wilson, W. R.; Pullen, S. M.; Denny, W. A. Structure-activity relationships for 4-nitrophenyl carbamates of 5-aminobenz[e]indoline minor groove alkylating agents as prodrugs for GDEPT in conjunction with E. coli nitroreductase. J. Med. Chem. 2003, 46, 2456-2466.
23. Alvaro, R. F.; Wislocki, P. G.; Miwa, G. T., Lu, A. Y. H. Drug residue formation from ronidazole, a 5-nitroimidazole. VIII. Identification of the 2-methylene position as a site of protein alkylation. Chem.-Biol. Interactions 1992, 82, 21-30.
24. Sinhababu, A. K.; Thakker, D. R. Prodrugs of anticancer agents. Advanced Drug Delivery Rev. 1996, 19, 241-273.
25. Prakash, S. R.; Correa, I. D.; Gan, L.-S.; Chism, J. P.; Arrendale, R. F.; Miwa, G. T.; Thakker, D. R. Tumor targeting by reductive activation of nitroimidazole carbamates. In Synth. Appl. Isot. Labeled Compd. 1994, Proc. Int. Symp., 5th, 1994; Allen, J., Voges, R., Eds.; Wiley: Chichester, U.K., 1995; 573-576.
26. Berry, J. M.; Watson, C. Y.; Whish, W. J. D.; Threadgill, M. D. 5-Nitrofuran-2-ylmethyl group as a potentially activated prodrug system. J. Chem. Soc., Perkin Trans. 1 1997, 1147-1156.
27. Everett, J. L.; Ross, W. C. J. Aryl-2-halogenoakylamines. Part II. J. Chem. Soc. 1949, 1972-1983.
28. Atwell, G. J.; Wilson, W. R.; Denny, W. A. Synthesis and cytotoxicity of novel amino analogues of the potent DNA alkylating agent seco-CBI-TMI. Bioorg. Med. Chem. Lett. 1997, 7, 1493-1496.
29. Atwell, G. J.; Tercel, M.; Boyd, M.; Wilson, W. R.; Denny, W. A. Synthesis and cytotoxicity of 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1, 2-dihydro-3H-benz[e]indole (amino-seco-CBI-TMI) and related 5-alkylamino analogues: New DNA minor groove alkylating agents. J. Org. Chem. 1998, 63, 9414-9420.
30. Denny, W. A.; Wilson, W. R.; Considerations for the design of nitrophenyl mustards as agents with selective toxicity for hypoxic tumor cells. J. Med. Chem. 1986, 29, 879-887.
31. Gieseg, M. A.; Matejovic, J.; Denny, W. A. Comparison of the patterns of DNA alkylation by phenol and amino-seco-CBI-TMI compounds: Use of a PCR method for the facile preparation of single end-labeled double-stranded DNA. Anti-Cancer Drug Design 1999, 14, 77-84.
32. Durand, R. G. The influence of microenvironmental factors during cancer therapy. In Vivo 1994, 8, 691-702.
33. Hay, M. P.; Sykes, B. M.; Denny, W. A.; Wilson, W. R. A 2-nitroimidazole carbamate prodrug of 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1, 2-dihydro-3H-benz[e]-indole (amino-seco-CBI-TMI) for use with ADEPT and GDEPT. Bioorg. Med. Chem. Lett. 1999, 9, 2237-2242.
34. Narcombe, P. J.; Norris, R. K. Substitution reactions of nitrothiophenes. III. Radical and ionic reactions of 4- and 5-nitro-2-thienyl-methyl and ethyl chlorides and acetates. Aust. J. Chem. 1979, 32, 2647-2658.
35. Hay, M. P.; Wilson, W. R.; Denny, W. A. Design, synthesis and evaluation of imidazolylmethyl carbamate prodrugs of alkylating agents. Tetrahedron 2000, 56, 645-657.
36. Tercel, M.; Lee, A. E.; Hogg, A.; Anderson, R. F.; Lee, H. H.; Siim, B. G.; Denny, W. A.; Wilson, W. R. Hypoxia-selective antitumor agents. 16. Nitroarylmethyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine. J. Med. Chem. 2001, 44, 3511-3522.
37. Baker, D. C.; Putt, S. R.; Showalter, H. D. H. Studies related to the total synthesis of pentostatin. Approaches to the synthesis of (8R)-3,6,7,8-tetrahydroimidazo-[4,5-d][1,3]diazepin-8-ol and N-3 alkyl congeners. J. Heterocycl. Chem. 1983, 20, 629-634.
38. Cheng, C.-C. Pyrazoles. II. Reactions of 1-methyl-5-amino-4-pyrazolecarboxamide and nitrous acid. Introduction of a nitro group at position 5 in the pyrazole ring. J. Heterocycl. Chem. 1968, 5, 195-197.
39. Ross, W. J.; Jamieson, W. B.; McCowen, M. C. Antiparasitic nitroimidazoles. 1. Some 2-styryl-5-nitroimidazoles. J. Med. Chem. 1972, 15, 1035-1039.
40. Dubrovchik, G. M.; King, H. D.; Pham-Kaplita, K. Efficient Mitomycin C coupling with stable p-nitrophenyl-benzyl carbonates using hydroxybenzotriazole as a catalytic additive. Tetrahedron Lett. 1997, 38, 5261-5264.
41. Anderson, W. K.; Bhattacharjee, D.; Houston, D. M. Design, Synthesis, Antineoplastic Activity, and Chemical Properties of Bis(carbamate) Derivatives of 4,5-Bis(hydroxymethyl)imidazole. J. Med. Chem. 1989, 32, 119-127.
42. Meisel, D.; Czapski, G. One-electron-transfer equilibria and redox potentials of radicals studied by pulse radiolysis. J. Phys. Chem. 1975, 79, 1503-1509.
43. Wardman, P. Some reactions and properties of nitro radical-anions important in biology and medicine. Environ. Health Perspect. 1985, 64, 309-320.
44. Wardman, P. Reduction potentials of one-electron couples involving free radicals in aqueous solution. J. Chem. Phys. Chem. Ref. Data 1989, 18, 1637-1755.
45. Bryant, C.; DeLuca, M. Purification and characterization of an oxygen-insensitive NAD(P)H nitroreductase from Enterobacter cloacae. J. Biol. Chem. 1991, 266, 4119-4125.
46. Nivinskas, H.; Koder, R. L.; Anusevicius, Z.; Sarlauskas, J.; Miller, A.-F.; Cenas, N. Quantitative structure-activity relationships in two-electron reduction of nitroaromatic compounds by Enterobacter cloacae NAD(P)H:nitroreductase. Arch. Biochem. Biophys. 2001, 385, 170-178.
47. Stratford, I. J.; Williamson, C.; Hoe, S.; Adams, G. E. Radiosensitizing and cytotoxicity studies with CB1954 (2,4-dinitro-5-aziridinylbenzamide). Radiat. Res. 1981, 88, 502-509.
48. Palmer, B. D.; Wilson, W. R.; Pullen, S. M.; Denny, W. A. Hypoxia-selective antitumor agents. 3. Relationships between structure and cytotoxicity against cultured tumor cells for substituted N,N-bis(2-chloroethyl)anilines. J. Med. Chem. 1990, 33, 112-121.
49. Wilson, W. R.; Pullen, S. M.; Hogg, A.; Hobbs, S. M.; Pruijn, F. B.; Hicks, K. O. In vitro and in vivo models for evaluation of GDEPT: Quantifying bystander killing in cell cultures and tumors. In Suicide Gene Therapy: Methods and Protocols for Cancer; Springer, C. J., Ed.; Humana Press: Totowa, New Jersey, 2003; in press.
50. Hicks, K. O.; Pruijn, F. B.; Sturman, J. R.; Denny, W. A.; Wilson, W. R. Multicellular resistance to tirapazamine is due to restricted extravascular transport: A pharmacokinetic/pharmacodynamic study in multicellular layers. Cancer Res. 2003, (in press).
51. Bochwic, B.; Frankowski, A.; Kuswik, G.; Seliga, C. 4,5-Disubstituted imidazoles. Part I. 4-(Hydroxymethyl)-5-nitroimidazole, 4-formyl-5-nitroimidazole and their N-substituted derivatives. Polish J. Chem. 1981, 55, 1055-1061.
52. Friedlos, F.; Court, S.; Ford, M.; Denny, W. A.; Springer, C. J. Gene-directed enzyme prodrug therapy: Quantitative bystander cytotoxicity and DNA damage induced by CB1954 in cells expressing bacterial nitroreductase. Gene Ther. 1998, 5, 105-112.
53. Finlay, G. J.; Baguley, B. C.; Wilson, W. R. A semiautomated microculture method for investigating growth inhibitory effects of cytotoxic compounds on exponentially growing carcinoma cells. Anal. Biochem. 1984, 139, 272-277.
54. Palmer, B. D.; Wilson, W. R.; Anderson, R. F.; Boyd, M.; Denny, W. A. Hypoxia-selective antitumor agents. 14. Synthesis and hypoxic cell cytotoxicity of regioisomers of the hypoxia-selective cytotoxin 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide. J. Med. Chem. 1996, 39, 2518-2528.
55. Van Leeuwen, J. W.; Van Dijk, C.; Veeger, C. A pulse radiolysis study of the reduction of flavodoxin from Megasphaera elsdenii by viologen radicals. Eur. J. Biochem. 1983, 135, 601-607.
56. Stekhan, E.; Kuwana, T. Spectroelectrochemical study of mediators. I. Bipyridylium salts and their electron-transfer rates to cytochrome C. Ber. Bunsen-Ges. Phys. Chem. 1974, 78, 253-259.