Optimization of Alkylating Agent Prodrugs Derived from Phenol and Aniline Mustards: A New Clinical Candidate Prodrug (ZD2767) for Antibody-Directed Enzyme Prodrug Therapy (ADEPT)

Journal of Medicinal Chemistry

Volumn 38, Issue 26, 1995, Pages 5051-5065

  Springer, Caroline J ^a   Dowell, Robert ^b   Burke, Philip J ^c   Hadley, Elma ^b   Davies, D Huw ^b   Blakey, David C ^b   Melton, Roger G ^d   Niculescu Duvaz, Ion ^a  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^b ASTRAZENECA   (United Kingdom)

^c CHARING CROSS HOSPITAL   (United Kingdom)

^d PUBLIC HEALTH ENGLAND   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALKYLATING AGENT; ANILINE MUSTARD; ANTIBODY CONJUGATE; PRODRUG; UNCLASSIFIED DRUG; ZD 2767;

ALKYLATION; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ANTIBODY DETECTION; ANTIBODY DIRECTED ENZYME PRODRUG THERAPY; ARTICLE; CANCER CHEMOTHERAPY; DRUG EFFICACY; DRUG STABILITY; DRUG STRUCTURE; ENZYME ACTIVATION; NONHUMAN; STRUCTURE ANALYSIS;

ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS, ALKYLATING; CELL SURVIVAL; GAMMA-GLUTAMYL HYDROLASE; HUMANS; KINETICS; MAGNETIC RESONANCE SPECTROSCOPY; MOLECULAR STRUCTURE; NITROGEN MUSTARD COMPOUNDS; PRODRUGS; TUMOR CELLS, CULTURED;

EID: 0029621825     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm00026a013     Document Type: Article

References (24)

1. Frei, E., III. Curative cancer chemotherapy. Cancer Res. 1985, 45, 6532-6538.
2. Bagshawe, K. D. Antibody directed enzymes revive anti-cancer prodrug concept. Br. J. Cancer 1987, 56, 531-532.
3. Bagshawe, K. D.; Springer, C. J.; Searle, F.; Antoniw, P.; Sharma, S. K.; Melton, R. G.; Sherwood, R. F. A cytotoxic agent can be generated selectively at cancer sites. Br. J. Cancer 1988, 58, 700-703.
4. Teicher, B. A.; Frei, E., III, Development of alkylating agent resistant human tumor cell lines. Cancer Chemother. Pharmacol. 1988, 21, 292-298.
5. Springer, C. J.; Antoniw, P.; Bagshawe, K. D.; Searle, F.; Bisset, G. M. F.; Jarman, M. Novel prodrugs which are activated to cytotoxic alkylating agents by carboxypeptidase G2. J. Med. Chem. 1990, 33, 677-681.
6. Mann, J.; Haase-Held, M.; Springer, C. J.; Bagshawe, K. D. Synthesis of an N-mustard prodrug. Tetrahedron 1990, 46, 5377-5382.
7. Springer, C. J. CMDA, an antineoplastic prodrug. Drugs Future 1993, 18, 212-215.
8. Springer, C. J.; Niculescu-Duvaz, I.; Pedley, R. B. Novel prodrugs of alkylating agents derived from 2-fluoro- and 3-fluoro benzoic acids for antibody-directed enzyme prodrug therapy. J. Med. Chem. 1994, 37, 2361-2370.
9. Sharma, S. K.; Boden, J. A.; Springer, C. J.; Burke, P. J.; Bagshawe, K. D. Antibody-directed prodrug therapy (ADEPT). A three-phase study in ovarian tumour xenografts. Cell Biophys. 1994, 24/25, 219-228.
10. Eccles, S.; Court, W. J.; Box, G. A.; Dean, C. J.; Melton, R. G.; Springer, C. J. Regression of established breast carcinoma xenografts with antibody-directed enzyme prodrug therapy against C-erbB2 pl85. Cancer Res. 1994, 54, 5171-5177.
11. Bagshawe, K. D.; Sharma, S. K.; Springer, C. J.; Antoniw, P. Antibody-Directed Enzyme Prodrug Therapy (ADEPT): Pilot Scale Clinical Trial. Tumour Targeting 1995, 1, 17-29.
12. Bagshawe, K. D.; Sharma, S. K.; Springer, C. J.; Antoniw, P.; Boden, J. A.; Rogers, G. T.; Burke, P. J.; Melton, R. G.; Sherwood, R. F. Antibody-Directed Enzyme Prodrug Therapy (ADEPT): Clinical report. Disease Markers 1991, 9, 233-238.
13. Bagshawe, K. D.; Sharma, S. K.; Springer, C. J.; Rogers, G. T. Antibody-Directed Enzyme Prodrug Therapy (ADEPT): A review of some theoretical, experimental and clinical aspects. Anal. Oncol. 1994, 5, 879-891.
14. Springer, C. J.; Poon, G. K.; Sharma, S. K.; Bagshawe, K. D. Identification of prodrug, active drug and metabonates in an ADEPT clinical study. Cell Biophys. 1993, 22, 1-8.
15. Springer, C. J.; Niculescu-Duvaz, I.; Mauger, A. B.; Connors, T. A.; Burke, P. J.; Davies, D. H.; Dowell, R. I.; Boyle, F. T.; Blakey, D. C.; Melton, R. G. In New Antibody Technology and the Emergence of Useful Cancer Therapy, Begent, R., Hamlin, A., Eds.; Royal Society of Medicine Press: London, 1995; pp 7577.
16. Dowell, R.; Springer, C. J.; Davies, D. H.; Hadley, E. M.; Burke, P. J.; Boyle, F. T.; Melton, R. G.; Connors, T. A.; Blakey, D. C.; Mauger, A. B. New mustard prodrugs for antibody directed enzyme prodrug therapy (ADEPT). Alternative to amide link. J. Med. Chem., accepted for publication.
17. Springer, C. J.; Niculescu-Duvaz, I. Antidody-directed enzyme prodrug therapy (ADEPT) with mustard prodrugs. Anticancer Drug Des. 1995, 10, 361-372.
18. Niculescu-Duvaz, I.; Springer, C. J. Adamantylanyloxycarbo- nyl: a novel protecting group for phenols carrying strongly electron-withdrawing substituents. J. Chem. Res., Synop. 1994, 242-243.
19. Springer, C. J.; Antoniw, P.; Bagshawe, K. D.; Wilman, D. E. V. Comparison of half-lives and cytotoxicity of N-mesyloxyethyl- and N-chloroethyl-4-amino benzoyl compounds, products of prodrugs in antibody-directed enzyme prodrug therapy (ADEPT). Anticancer Drug Des. 1991, 6, 467-479.
20. Panthananical, A.; Hansch, C.; Leo, A.; Quinn, F. R. Structure- activity relationships in antitumor aniline mustards. J. Med. Chem. 1978, 21, 16-26.
21. Ross, W. C. J. Biological alkylating agents; Butterworths: London, 1962.
22. Bohm, S.; Decouzon, M.; Exner, O.; Gal, J. F.; Maria, C. P. Sterically hindered resonance in methyl-substituted anilines in the gas phase. J. Org. Chem. 1994, 59, 8127-8131.
23. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, D.; Warren, J. T.; Bokedch, H.; Kenney, S.; Boyd, M. R. New colorimetric cytotoxicity assay for anticancer screening. J. Natl. Cancer Inst. 1990, 82, 1107-1112.
24. Springer, C. J.; Bagshawe, K. D.; Sharma, S. K.; Searle, F.; Boden, J. A.; Antoniw, P.; Burke, P. J.; Rogers, G. T.; Sherwood, R. F.; Melton, R. G. Ablation of human choriocarcinoma xenografts in nude mice by Antibody-Directed Enzyme Prodrug Therapy (ADEPT) with three novel compounds. Eur. J. Cancer 1991, 27, 1361-1366.