Structure-based design of lipophilic quinazoline inhibitors of thymidylate synthase

Journal of Medicinal Chemistry

Volumn 39, Issue 4, 1996, Pages 904-917

  Jones, Terence R ^a,b   Varney, Michael D ^a   Webber, Stephen E ^a   Lewis, Kathleen K ^a   Marzoni, Gifford P ^a   Palmer, Cindy L ^a   Kathardekar, Vinit ^a   Welsh, Katharine M ^a   Webber, Stephanie ^a   Matthews, David A ^a   Appelt, Krzysztof ^a   Smith, Ward W ^a   Janson, Cheryl A ^a   Villafranca, J E ^a   Bacquet, Russell J ^a   Howland, Eleanor F ^a   Booth, Carol L J ^a   Herrmann, Steven M ^a   Ward, Robert W ^a   White, Jennifer ^a   Moomaw, Ellen W ^a   Bartlett, Charlotte A ^a   Morse, Cathy A ^a   more..

^a AGOURON PHARMACEUTICALS INC   (United States)

^b Atelier Pharmaceuticals Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

10 PROPARGYL 5,8 DIDEAZAFOLIC ACID; [4 [N [(3,4 DIHYDRO 2 METHYL 6 QUINAZOLINYL)METHYL] N (2 PROPYNYL)AMINO]PHENYL] PHENYL SULFONE; ENZYME INHIBITOR; QUINAZOLINE DERIVATIVE; THYMIDYLATE SYNTHASE; THYMIDYLATE SYNTHASE INHIBITOR; UNCLASSIFIED DRUG; URIDINE PHOSPHATE;

ADENOCARCINOMA; ANIMAL TISSUE; ARTICLE; DRUG CYTOTOXICITY; DRUG DESIGN; ENZYME ACTIVE SITE; ENZYME INHIBITION; ESCHERICHIA COLI; GROWTH INHIBITION; HUMAN; HUMAN TISSUE; LEUKEMIA; MOUSE; NONHUMAN; X RAY CRYSTALLOGRAPHY;

ADENOCARCINOMA; ANIMALS; ANTINEOPLASTIC AGENTS; BINDING SITES; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; ENZYME INHIBITORS; ESCHERICHIA COLI; FOLIC ACID ANTAGONISTS; HUMANS; LEUKEMIA; LEUKEMIA L1210; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; PROTEIN CONFORMATION; QUINAZOLINES; STRUCTURE-ACTIVITY RELATIONSHIP; THYMIDYLATE SYNTHASE; TUMOR CELLS, CULTURED;

EID: 13344270889     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9502652     Document Type: Article

References (53)

1. Berman, E. M.; Werbel, L. M. The renewed potential for folate antagonists in contemporary cancer chemotherapy. J. Med. Chem. 1991, 34, 479-485.
2. Jones, T. R.; Calvert, A. H.; Jackman, A. L.; Brown, S. J.; Jones, M.; Harrap, K.R. A potent antitumour quinazoline inhibitor of thymidylate synthetase: Synthesis, biological properties and therapeutic results in mice. Eur. J. Cancer 1981, 17, 11-19.
3. 10 substituent. J. Med. Chem. 1985, 28, 1468-1476.
4. 10-propargyl-5,8-dideazafolic acid, CB3717. J. Clin. Oncol. 1986, 4, 1245-1252.
5. 10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694 in mice. Br. J. Cancer 1991, 64, 833-838.
6. Jones, T. R.; Thornton, T. J.; Flinn, A.; Jackman, A. L.; Newell, D. R.; Calvert, A. H. Quinazoline antifolates inhibiting thymidylate synthase: 2-Desamino derivatives with enhanced solubility and potency. J. Med. Chem. 1989, 32, 847-852.
7. Jackman, A. L.; Newell, D. R.; Taylor, G. A.; O'Connor, B.; Hughes, L. R.; Calvert, A. H. 2-Desamino-10-propargyl-5,8-dideazafolic acid (desamino-CB3717), a thymidylate synthase inhibitor devoid of renal and hepatic toxicities in mice. Proc. Am. Assoc. Cancer Res. 1987, 28, 271.
8. Hughes, L. R.; Jackman, A. L.; Oldfield, J.; Smith, R. C.; Burrows, K. D.; Marsham, P. R.; Bishop, J. A. M.; Jones, T. R.; O'Connor, B. M.; Calvert, A. H. Quinazoline antifolate thymidylate synthase inhibitors: Alkyl, substituted alkyl, and aryl substituents in the C2 position. J. Med. Chem. 1990, 33, 3060-3067.
9. 10-propargyl-5,8-dideazafolic acid (ICI 198583). Biochem. Pharmacol. 1991, 42, 1885-1895.
10. Moran, R. G.; Colman, P. D.; Rosowsky, A.; Forsch, R. A.; Chan, K. K. Structural features of 4-amino antifolates required for substrate activity with mammalian folylpolyglutamate synthetase. Mol. Pharmacol. 1985, 27, 156-166.
11. 10-propargyl-5,8-dideazafolic acid (CB3717) polyglutamates in L1210 cells in vitro. Biochem. Pharmacol. 1988, 37, 4047-4054.
12. 10-propargyl-5,8-dideazafolic acid and related compounds in murine (L1210) and Human (W1L2) systems in vitro and in L1210 in vivo. Cancer Res. 1990, 50, 5212-5218.
13. Jackman, A. L.; Taylor, G. A.; Gibson, W.; Kimbell, R.; Brown, M.; Calvert, A. H.; Judson, I. R.; Hughes, L. R. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth In vitro and in vivo: A new agent for clinical study. Cancer Res. 1991, 51, 5579-5586.
14. Clarke, S.; Ward, J.; Planting, A.; Spiers, J.; Smith, R.; Verweij, J.; Judson, I. Phase I trial of ICI D1694: A novel thymidylate synthase inhibitor. Proc. Am. Assoc. Cancer Res. 1992, 33, 406.
15. Hagan, R. L.; Duch, D. S.; Smith, G. K.; Hanlon, M. H.; Shane, B.; Freisheim, J. H.; Hynes, J. B. Studies on the mechanism of antitumor action of 2-desamino-2-methyl-5,8-dideazaisofolic acid. Biochem. Pharmacol. 1991, 41, 781-787.
16. Duch, D. S.; Banks, S.; Dev, I. K.; Dickerson, S. H.; Ferone, R.; Heath, L. S.; Humphreys, J.; Knick, V.; Pendergast, W.; Singer, S.; Smith, G. K.; Waters, K.; Wilson, H. R. Biochemical and cellular pharmacology of 1843U89, a novel benzoquinazoline inhibitor of thymidylate synthase. Cancer Res 1993, 53, 810-818.
17. Albrecht, A. M.; Biedler, J. L. Acquired resistance of tumor cells to folate antagonists. In Folate Antagonists as Therapeutic Agents, Vol 1; Sirotnak, F. M., Burchall, J. J., Ensminger, W. B., Montgomery, J. A., Eds.; Academic Press: San Diego, 1984; pp 317-353.
18. Curt, G. A.; Jolivet, J.; Carney, D. N.; Bailey, B. D.; Drake, J. C.; Clendennin, N. J.; Chabner, B. A. Determinants of the sensitivity of human small-cell lung cancer cell lines to methotrexate. J. Clin. Invest. 1985, 76, 1323-1329.
19. McCloskey, D. E.; McGuire, J. J.; Russell, C. A.; Rowan, B. G.; Bertino, J. R.; Pizzorno, G.; Mini, E. Decreased folylpolyglutamate synthetase activity as a mechanism of methotrexate resistance in CCRF-CEM human leukemia sublines. J. Biol. Chem. 1991, 266, 6181-6187.
20. Rumberger, B. G.; Schmid, F. A.; Otter, G. M.; Sirotnak, F. M. Preferential selection during therapy in vivo by edatrexate compared to methotrexate of resistant L1210 cell variants with decreased folylpolyglutamate synthetase activity. Cancer Commun. 1990, 2, 305-310.
21. 10-propargyl-5,8-dideazafolic acid: A novel folate-based thymidylate synthase inhibitor. Cancer Res. 1992, 52, 1137-1143.
22. Appelt, K.; Bacquet, R. J.; Bartlett, C. A.; Booth, C. L. J.; Freer, S. T.; Fuhry, M. A. M.; Gehring, M. R.; Herrmann, S. M.; Rowland, E. F.; Janson, C. A.; Jones, T. R.; Kan, C.-C.; Kathardekar, V.; Lewis, K. K.; Marzoni, G. P.; Matthews, D. A.; Mohr, C.; Moomaw, E. W.; Morse, C. A.; Oatley, S. J.; Ogden, R. C.; Reddy, M. R.; Reich, S. H.; Schoettlin, W. S.; Smith, W. W.; Varney, M. D.; Villafranca, J. E.; Ward, R. W.; Webber, S.; Webber, S. E.; Welsh, K. M.; White, J. Design of enzyme inhibitors using iterative protein crystallographic analysis. J. Med. Chem. 1991, 34, 1925-1934.
23. Matthews, D. A.; Appelt, K.; Oatley, S. J.; Xuong, Ng. H. Crystal structure of Escherichia coli thymidylate synthase containing bound 5-fluoro-2′-deoxyuridylate and 10-propargyl-5,8-dideazafolate. J. Mol. Biol. 1990, 214, 923-936.
24. All small molecules were minimized using the semiempirical AM1 method: Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. AM1: A new general purpose quantum mechanical molecular model. J. Am. Chem. Soc. 1985, 107, 3902-3909. Modeling was conducted using Polygen Corp. Quanta program on a Silicon Graphics 4D70GT workstation.
25. Fitzhugh, A. L.; Fodor, S.; Kaufman, S.; Spiro, T. G. Resonance Raman spectroscopic evidence for alternative structures in the native ternary complex formed with thymidylate synthase. J. Am. Chem. Soc. 1986, 108, 7422-7424.
26. McClellan, A. L. Tables of Experimental Dipole Moments, Volume II; Rahara Enterprises: El Cerrito, CA, 1974.
27. Burley, S. K.; Petsko, G. A. Aromatic-aromatic interaction: A mechanism of protein structure stabilization. Science 1985, 229, 23-28.
28. Singh, J.; Thornton, J. M. The interaction between phenylalanine rings in proteins. FEBS Lett. 1985, 191, 1-6.
29. Hiberty, P. C.; Ohanessian, G. Valence-Bond Description of Conjugated Molecules. 3. The through-resonance concept in para-substituted nitrobenzenes. J. Am. Chem. Soc. 1984, 106, 6963-6968.
30. Waldron, W. R., Reid, E. E. The influence of sulfur on the color of azo dyes. J. Am. Chem. Soc. 1923, 45, 2399-2417.
31. Friedman, L.; Shechter, H. Dimethylformamide as a useful solvent in preparing nitriles from aryl halides and cuprous cyanide; improved isolation techniques. J. Org. Chem. 1961, 26, 2522-2524.
32. Brandsma, L.; Verkruijsse, H. D. Synthesis of Acetylenes, Allenes and Cumulenes; Elsevier: Amsterdam, 1981; pp 223-224.
33. Bourne, E. J.; Henry, S. H.; Tatlow, C. E. M.; Tatlow, J. C. Studies of trifluoroacetic atcid. Part VI. Trifluoroacetyl derivatives of amines. J. Chem. Soc. 1952, 4014-4019.
34. Garito, A. F.; Horner, C. J.; Kalyanaraman, P. S.; Desai, K. N. Synthesis of N-(nitrophenyl)amine substituted diacetylene monomers. Makromol. Chem. 1980, 181, 1605-1612.
35. Shein, S. M.; Solodova, K. V.; Govorchenko, V. I. Nucleophilic substitution in the aromatic series XXXIII, Effect of the nature of substituted atoms or groups on reaction rates for parasubstituted trifluoromethyl phenyl sulfones with sodium alcoholates and piperidines. J. Gen. Chem. USSR 1969, 39, 1603-1609.
36. Yagupol'skii, L. M.; Gruz, B. E. Synthesis of some derivatives of phenyl trifluoromethyl sulfide and phenyl trifluoromethyl sulfone. J. Gen. Chem. USSR 1961, 31, 1219-1223.
37. Hendrickson, J. B.; Bair, K. W. New methods for the synthesis of triflones. J. Org. Chem. 1977, 42, 3875-3878.
38. Hughes, L. R. Eur. Pat. Appl. 239 362 A2, September 30, 1987.
39. McNamara, D. J.; Berman, E. M.; Fry, D. W.; Werbel, L. M. Potent inhibition of thymidylate synthase by two series of nonclassical quinazolines. J. Med. Chem. 1990, 33, 2045-2051.
40. Jones, T. R.; Smithers, M. J.; Betteridge, R. F.; Taylor, M. A.; Jackman, A. L.; Calvert, A. H.; Davies, L. C.; Harrap, K. R. Quinazoline antifolates inhibiting thymidylate synthase: Variation of the amino acid. J. Med. Chem. 1986, 29, 1114-11189.
41. Epstein, J.; Rosenthal, R. W.; Ess, R. J. Use of γ-(4-nitrobenzyl)-pyridine as analytical reagent for ethylenimines and alkylating agents. Anal. Chem. 1955, 27, 1435-1439.
42. Leonard, N. J.; Sutton, L. E. The use of fluoro compounds in the determination of valency angles by electric dipole moment measurements. J. Am. Chem. Soc. 1948, 70, 1564-1571.
43. Kaplan, L. J.; Martin, J. C. Sulfuranes. IX. Sulfuranyl substituent parameters, substituent effects on the reactivity of dialkoxy-diarylsulfuranes in the dehydration of alcohols. J. Am. Chem. Soc. 1973, 95, 793-798.
44. Yung, D. K.; Forrest, T. P.; Manzer, A. R.; Gilroy, M. L. Reactions of benzenesulfonohydrazides and benzenesulfonamides with hydrogen chloride or hydrogen bromide in acetic acid. J. Pharm. Sci. 1977, 66, 1009-1012.
45. Adams, R.; Long, P. H.; Johanson, A. J. Sulfanilamide derivatives. J. Am. Chem. Soc. 1939, 61, 2342-2346.
46. Herkes, F. E.; Burton, D. J. Fluoro olefins. I. The synthesis of β-substituted perfluoro olefins. J. Org. Chem. 1967 32, 1311-1318.
47. 3H. J. Biol. Chem. 1967, 242, 109-113.
48. Cleland, W. W. The kinetics of enzyme-catalysed reactions with two or more substrates or products. II Inhibition: Nomenclature and theory. Biochim. Biophys. Acta 1963, 67, 173-187.
49. Perrella, F. W. EZ-FIT; Perrella Scientific: Springfield, PA, 1989.
50. Alley, M. C.; Scuderio, D. A.; Monks, A.; Hursey, M. L.; Czerwinski, M. J.; Fine, D. L.; Abbott, B. J.; Mayo, J. G.; Shoemaker, R. H.; Boyd, M. R. Feasability of drug screeening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 1988, 48, 589-601.
51. MTT is 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.
52. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 1983, 65, 55-63.
53. Kindly supplied by Dr. P. J. Houghton and Dr. J. A. Houghton, St. Jude Children's Research Hospital, Memphis, TN.