5-Deazafolate analogues with a rotationally restricted glutamate or ornithine side chain: Synthesis and binding interaction with folylpolyglutamate synthetase

Journal of Medicinal Chemistry

Volumn 42, Issue 18, 1999, Pages 3510-3519

  Rosowsky, Andre ^a   Forsch, Ronald A ^a   Null, Allison ^b   Moran, Richard G ^b  

^a HARVARD MEDICAL SCHOOL   (United States)

^b VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2,3 DIHYDRO 5 [N [ 2 AMINO 4 OXO 5,6,7,8 TETRAHYDROPYRIDO[2,3]PYRIMIDIN 6 YL]METHYLAMINO] 1 OXO 2 ISOINDOLYL]GLUTARIC ACID; FOLIC ACID DERIVATIVE; FOLYLPOLYGLUTAMATE SYNTHASE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; CATALYSIS; CELL COMPARTMENTALIZATION; CHO CELL; DRUG POTENCY; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME METABOLISM; HYDROGENATION; LYSOSOME MEMBRANE; MOLECULAR INTERACTION; NONHUMAN;

CELL DIVISION; ENZYME INHIBITORS; FOLIC ACID; FOLIC ACID ANTAGONISTS; GLUTAMIC ACID; HUMANS; ORNITHINE; PEPTIDE SYNTHASES; RECOMBINANT PROTEINS;

EID: 0033539085     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9807205     Document Type: Article

References (99)

1. McGuire, J. J.; Coward, J. K. In Folates and Pterins; Blakley, R. L., Benkovic, S. J., Eds.; John Wiley & Sons: New York, 1984; Vol. 1, pp 135-190.
2. Shane, B. Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism. Vitam. Horm. 1989, 45, 263-335.
3. Fabre, I.; Fabre, G.; Goldman, I. D. Polyglutamylation, an important element in methotrexate cytotoxicity and selectivity in tumor versus murine granulocyte progenitor cells in vitro. Cancer Res. 1984, 44, 3190-3195.
4. Chabner, B. A.; Allegra, C. J.; Curt, G. A.; Clendeninn, N. J.; Baram, J.; Koizumi, S.; Drake, J. C.; Jolivet, J. Polyglutamation of methotrexate. Is methotrexate a prodrug? J. Clin. Invest. 1985, 76, 907-912.
5. (a) Pizzorno, G.; Mini, E.; Coronnello, M.; McGuire, J. J.; Moroson, B. A.; Cashmore, A. R.; Dreyer, R. N.; Lin, J. T.; Mazzeri, T.; Periti, P.; Bertino, J. R. Impaired polyglutamylation of methotrexate as a cause of resistance in CCRF-CEM cells after short-term, high-dose treatment with this drug. Cancer Res. 1988, 48, 2149-2155.
6. (b) Pizzorno, G.; Chang, Y.-M.; McGuire, J. J.; Bertino, J. R. Inherent resistance of human squamous carcinoma cell lines to methotrexate as a result of decreased polyglutamylation of this drug. Cancer Res. 1989, 49, 5275-5280.
7. (c) Li, W.-W.; Lin, J. T.; Tong, W. P.; Trippett, T. M.; Brennan, M. F.; Bertino, J. R. Mechanisms of natural resistance to antifolates in human soft tissue sarcomas. Cancer Res. 1992, 52, 1434-1438.
8. (a) Rumberger, B. G.; Barrueco, J. R.; Sirotnak, F. M. Differing specificities for 4-aminofolate analogues of folylpolyglutamate synthetase from tumors and proliferative intestinal epithelium of the mouse with significance for selective antitumor action. Cancer Res. 1990, 50, 4639-4643.
9. (b) 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 variants with decreased folylpolyglutamate synthetase activity. Cancer Commun. 1990, 2, 305-310.
10. (a) Barrueco, J. R.; Sirotnak, F. M. Evidence for the facilitated transport of methotrexate polyglutamates into lysosomes derived from S180 cells. J. Biol. Chem. 1991, 266, 11732-11737.
11. (b) Barrueco, J. R.; O'Leary, D. F.; Sirotnak, F. M. Metabolic turnover of methotrexate polyglutamates in lysosomes derived from S180 cells: definition of a two-step process limited by mediated lysosomal permeation of polyglutamates and activating reduced sulfhydryl compounds. J. Biol. Chem. 1992, 267, 15356-15361.
12. (a) Samuels, L. L.; Goutas, L. J.; Priest, D. G.; Piper, J. R.; Sirotnak, F. M. Hydrolytic cleavage of methotrexate γ-polyglutamates by folylpolyglutamyl hydrolase derived from various tumors and normal tissues of the mouse. Cancer Res. 1986, 46, 2230-2235.
13. (a) Yao, R.; Rhee, M. S.; Galivan, J. Effects of γ-glutamyl hydrolase on folyl and antifolylpolyglutamates in cultured H35 hepatoma cells. Mol. Pharmacol. 1995, 48, 505-511.
14. (b) Yao, R.; Nimec, Z.; Tyan, T. J.; Galivan, J. Identification, cloning, and sequencing of a cDNA coding for rat γ-glutamyl hydrolase. J. Biol. Chem. 1996, 271, 8525-8528.
15. Moran, R. Characterization of the function of mammalian folylpolyglutamate synthetase (FPGS). Adv. Exp. Med. Biol. 1983, 163, 327-339.
16. McBurney, M. W.; Whitmore, G. F. Isolation and biochemical characterization of folate deficient mutants of Chinese hamster cells. Cell 1974, 2, 173-182.
17. Liu, Y.; Raghunathan, K.; Hill, C.; He, Y.; Bunni, M. A.; Barredo, J.; Priest, D. G. Effect of antisense-based folylpoly-γ-glutamate synthetase down-regulation on reduced folates and cellular proliferation in CCRF-CEM cells. Biochem. Pharmacol. 1998, 55, 2031-2037.
18. (a) 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.
19. (b) George, S.; Cichowicz, D. J.; Shane, B. Mammalian folylpoly-γ-glutamate synthetase. 3. Specificity for folate analogues. Biochemistry 1987, 26, 522-529.
20. (c) Moran, R. G.; Colman, P. D.; Rosowsky, A. Structural requirements for the activity of antifolates as substrates for mammalian folylpolyglutamate synthetase. NCI Monogr. 1987, 5, 133-138.
21. (d) McGuire, J. J.; Piper, J. R.; Coward, J. K.; Galivan, J. Folate analogue nonsubstrates and inhibitors of folylpolyglutamate synthetase as potential cancer chemotherapy drugs. NCI Monogr. 1987, 5, 139-144.
22. (e) Rosowsky, A.; Moran, R. G.; Freisheim, J. H.; Bader, H.; Forsch, R. A.; Solan, V. C. Synthesis and biologic activity of new side-chain-altered methotrexate and aminopterin analogues with dual inhibitory activity against dihydrofolate reductase and folylpolyglutamate synthetase. NCI Monogr. 1987, 5, 145-152.
23. (a) Cichowicz, D. J.; Hynes, J. B.; Shane, B. Substrate specificity of mammalian folylpoly-γ-glutamate synthetase for 5,8-dideazafolates and 5,8-dideaza analogues of aminopterin. Biochim. Biophys. Acta 1988, 957, 363-369.
24. (b) Coll, R. J.; Cesar, D.; Hynes, J. B.; Shane, B. In vitro metabolism of 5,8-dideazafolates and 5,8-dideazaisofolates by mammalian folypoly-γ-glutamate synthetase. Biochem. Pharmacol. 1991, 42, 833-838.
25. 9-substituted analogues. J. Med. Chem. 1991, 34, 606-610.
26. (d) Patil, S. A.; Shane, B.; Freisheim, J. H.; Singh, S. K.; Hynes, J. B. Inhibition of mammalian folylpolyglutamate synthetase and human dihydrofolate reductase by 5,8-dideaza analogues of folic acid and aminopterin bearing a terminal L-ornithine. J. Med. Chem. 1989, 32, 1559-1565.
27. Moran, R. G.; Colman, P. D.; Jones, T. R. Relative substrate activities of structurally related pteridine, quinazoline, and pyrimidine analogues for mouse liver folylpolyglutamate synthetase. Mol. Pharmacol. 1989, 36, 736-743.
28. (a) Taylor, E. C.; Harrington, P. J.; Fletcher, S. R.; Beardsley, G. P.; Moran, R. G. Synthesis of the antileukemic agents 5,10-dideazaaminopterin and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin. J. Med. Chem. 1986, 28, 914-921.
29. 10-substituted analogues. J. Med. Chem. 1989, 32, 1517-1522.
30. (c) Beardsley, G. P.; Moroson, B. A.; Taylor, E. C.; Moran, R. G. A new folate antimetabolite, 5,10-dideaza-5,6,7,8-tetrahydrofolate, is a potent inhibitor of de novo purine synthesis. J. Biol. Chem. 1989, 264, 328-333.
31. (d) Moran, R. G.; Baldwin, S. W.; Taylor, E. C.; Chih, C. The 6S-and 6R-diastereomers of 5,10-dideaza-5,6,7,8-tetrahydrofolate are equiactive inhibitors of de novo purine synthesis. J. Biol. Chem. 1989, 264, 21047-21051.
32. (e) Habeck, L. L.; Mendelsohn, L. R.; Shih, C.; Taylor, E. C.; Colman, P. D.; Gossett; Leitner, T. A.; Schultz, R. M.; Andis, S. L.; Moran, R. G. Substrate specificity of mammalian folylpolyglutamate synthetase for 5,10-dideazatetrahydrofolate analogues. Mol. Pharmacol 1995, 48, 326-333.
33. Varney, M. D.; Palmer, C. L.; Romines III, W. H.; Boritzky, T.; Margosiak, S. A.; Almassy, R.; Janson, C. A.; Bartlett, C.; Howland, E. J.; Ferre, R. Protein structure-based design, synthesis, and biological evaluation of 5-thia-2,6-diamino-4(3H)-oxopyrimidines: potent inhibitors of glycinamide ribonucleotide transformylase with potent cell growth inhibition. J. Med. Chem. 1997, 40, 2502-2524.
34. (a) Taylor, E. C.; Kuhnt, D.; Shih, C.; Rinzel, S. M.; Grindey, G. B.; Barredo, J.; Jannatipour, M.; Moran, R. G. A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidinyl-5-ethyl]-benzoyl]- L-glutamic acid, is an inhibitor of thymidylate synthase. J. Med. Chem. 1992, 35, 4450-4454.
35. (b) Itoh, F.; Russello, O.; Akimoto, H.; Beardsley, G. P. Novel pyrrolo[2,3-d]pyrimidine antifolate TNP-351: cytotoxic effect on methotrexate-resistant CCRF-CEM cells and inhibition of transformylases of de novo purine biosynthesis. Cancer Chemother. Pharmacol. 1994, 34, 273-279.
36. (c) McGuire, J. J.; Bergoltz, V. V.; Heitzman, K. J.; Haile, W. H.; Russell, C. A.; Bolanowska, W. A.; Kotake, Y.; Haneda, T.; Nomura, H. Novel 6,5-fused ring heterocyclic antifolates: biochemical and biological characterization. Cancer Res. 1994, 54, 2673-2679.
37. (d) Gangjee, A.; Devraj, R.; McGuire, J. J.; Kisliuk, R. L.; Queener, S. F.; Barrows, L. R. Classical and nonclassical furo[2,3-d]pyrimidines as novel antifolates: synthesis and biological activities. J. Med. Chem. 1994, 37, 1169-1176.
38. (e) Gangjee, A.; Mavandadi, F.; Queener, S. F.; McGuire, J. J. Novel 2,4-diamino-5-substituted-pyrrolo[2,3-d]pyrimidines as classical and nonclassical antifolate inhibitors of dihydrofolate reductases. J. Med. Chem. 1995, 38, 2158-2165.
39. (f) Gangjee, A.; Devraj, R.; McGuire, J. J.; Kisliuk, R. L. Effect of bridge region variation on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines. J. Med. Chem. 1995, 38, 3798-3805.
40. (a) Kelley, J. L.; McLean, E. W.; Cohn, N. K.; Edelstein, M. P.; Duch, D. S.; Smith, G. K.; Hanlon, M. H.; Ferone, R. Synthesis and biological activity of an acyclic analogue of 5,6,7,8-tetrahydrofolic acid, N-[4-[[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]benzoyl-L- glutamic acid. J. Med. Chem. 1990, 33, 561-567.
41. (b) Bigham, E. C.; Hodson, S. J.; Mallory, W. R.; Wilson, D.; Duch, D. S.; Smith, G. K.; Ferone, R. Synthesis and biological activity of open-chain analogues of 5,6,7,8-tetrahydrofolic acid - potential antitumor agents. J. Med. Chem. 1992, 35, 1399-1410.
42. (c) Mullen, R. J.; Keith, B. R.; Bigham, E. C.; Duch, D. S.; Ferone, R.; Heath, L. S.; Singer, S.; Waters, K. A.; Wilson, H. R. In vivo antiumor activity and metabolism of a series of 5-deazaacyclotetrahydrofolate (5-DACTHF) analogues. Biochem. Pharmacol. 1992, 1627-1634.
43. Sanghani, P. C.; Jackman, A.; Evans, V. R.; Thornton, T.; Hughes, L.; Calvert, A. H.; Moran, R. G. A strategy for the design of membrane-permeable folylpoly-γ-glutamate synthetase inhibitors: "bay-region"-substituted 2-desamino-2-methyl-5,8-dideazafolate analogues. Mol. Pharmacol. 1994, 45, 341-351.
44. (a) Matsuoka, H.; Kato, N.; Tsuji, K.; Maruyama, N.; Suzuki, H.; Mihara, M.; Takeda, Y.; Yano, K. Antirheumatic agents. I. Novel methotrexate derivatives bearing an indoline moiety. Chem. Pharm. Bull. 1996, 44, 1332-1337.
45. (b) Matsuoka, H.; Ohi, N.; Mihara, M.; Susuki, H.; Miyamoto, K.; Maruyama, N.; Tsuji, K.; Kato, N.; Akimoto, T.; Takeda, Y.; Yano, K.; Kuroki, T. Antirheumatic agents: novel methotrexate derivatives bearing a benzoxazine ring or benzothiazine moiety. J. Med. Chem. 1997, 40, 105-111.
46. Piper, J. R.; Johnson, C. A.; Maddry, J. A.; Malik, N. D.; McGuire, J. J.; Otter, G. M.; Sirotnak, F. M. Studies on analogues of classical antifolates bearing the naphthoyl group in place of benzoyl in the side chain. J. Med. Chem. 1993, 36, 4161-4171.
47. Rosowsky, A.; Bader, H.; Kohler, W.; Freisheim, J. H.; Moran, R. G. Methotrexate analogues. 34. Replacement of the glutamate moiety in methotrexate and aminopterin by long-chain 2-aminoalkanedioic acids. J. Med. Chem. 1988, 31, 1338-1344.
48. (a) Rosowsky, A.; Freisheim, J. H.; Moran, R. G.; Solan, V. C.; Bader, H.; Wright, J. E.; Radike-Smith, M. Methotrexate analogues. 26. Inhibition of dihydrofolate reductase and folylpolyglutamate synthetase activity and in vitro tumor cell growth by methotrexate and aminopterin analogues containing a basic amino acid side-chain. J. Med. Chem. 1988, 29, 655-660.
49. (b) Clarke, L.; Rosowsky, A.; Waxman, D. J. Inhibition of human liver folylpolyglutamate synthetase by non-γ-glutamylatable antifolate analogues. Mol. Pharmacol. 1987, 31, 122-127.
50. (c) Rosowsky, A.; Forsch, R. A.; Bader, H.; Freisheim, J. H. Synthesis and in vitro biological activity of new deaza analogues of folic acid, aminopterin, and methotrexate with an L-ornithine side chain. J. Med. Chem. 1991, 34, 1447-1454.
51. (d) Rosowsky, A.; Forsch, R. A.; Reich, V. E.; Freisheim, J. H.; Moran, R. G. Side chain modified 5-deazafolate and 5-deazatetrahydrofolate analogues as mammalian folylpolyglutamate synthetase and glycinamide ribonucleotide formyltransferase inhibitors: synthesis and in vitro biological evaluation. J. Med. Chem. 1992, 35, 1578-1588.
52. (e) Rosowsky, A.; Forsch, R. A.; Moran, R. G. Inhibition of folylpolyglutamate synthetase by substrate analogues with an ornithine side chain. J. Heterocycl Chem. 1996, 33, 1355-1361.
53. (a) McGuire, J. J.; Hsieh, P.; Franco, C. T.; Piper, J. R. Folylpolyglutmate synthetase inhibition and cytotoxic effects of methotrexate analogues containing 2,ω-diaminoalkanoic acids. Biochem. Pharmacol. 1986, 35, 2607-2613.
54. (b) McGuire, J. J.; Bolanowska, W. E.; Piper, J. R. Structural specificity of inhibition of human folylpolyglutamate synthetase by ornithine-containing folate analogues. Biochem. Pharmacol. 1988, 37, 3931-3939.
55. (a) Patil, S. A.; Shane, B.; Freisheim, J. H.; Singh, S.; Hynes. J. B. Inhibition of mammalian folylpolyglutamate synthetase and human dihydrofolate reductase by 5,8-dideaza analogues of folic acid and aminopterin bearing a terminal L-ornithine. J. Med. Chem. 1989, 32, 1559-1565.
56. α-(5-deaza-5,6,7,8-tetrahydropteroyl)-L-ornithine. J. Med. Chem. 1992, 35, 2002-2006.
57. (c) Hynes, J. B.; Singh, S. K.; Fetzer, O.; Shane, B. Inhibition of hog liver folylpolyglutamate synthetase by 5-substituted 5,8-dideaza analogues of folic acid bearing a terminal L-ornithine residue. J. Med. Chem. 1992, 35, 4078-4085.
58. 10-methylpteroyl-D,L-homocysteic acid and its dual inhibition of dihydrofolate reductase and folyl polyglutamate synthetase. Biochem. Pharmacol. 1984, 33, 155-162.
59. (b) Rosowsky, A.; Forsch, R. A.; Freisheim, J. H.; Moran, R. G.; Wick, M. Methotrexate analogues. 19. Replacement of the glutamate side-chain in classical antifolates by L-homocysteic and L-cysteic acids: effect on enzyme inhibition and antitumor activity. J. Med. Chem. 1984, 27, 600-604.
60. Rosowsky, A.; Moran, R. G.; Forsch, R. A.; Radike-Smith, M.; Colman, P. D.; Wick, M. M.; Freisheim, J. H. Methotrexate analogues. 27. Dual inhibition of dihydrofolate reductase and folylpolyglutamate synthetase by methotrexate and aminopterin analogues with a γ-phosphonate group in the side chain. Biochem. Pharmacol. 1988, 35, 3327-3333.
61. Tsukamoto, T.; Haile, W. H.; McGuire, J. J.; Coward, J. K. Synthesis and biological evaluation of Nα-(4-amino-4-deoxy-10-methylpteroyl)-DL-4,4-difluoroornithine. J. Med. Chem. 1996, 39, 2536-2540.
62. (a) Moran, R. G.; Colman, P. D.; Harvison, P. J.; Kalman, T. I. Evaluation of pteroyl-S-alkylhomocysteine sulfoximines as inhibitors of mammalian folylpolyglutamate synthetase. Biochem. Pharmacol. 1988, 37, 1997-2003.
63. (b) Mao, Z.; Pan, J.; Kalman, T. I. Design and synthesis of histidine analogues of folic acid and methotrexate as potential folylpolyglutamate synthetase inhibitors. J. Med. Chem. 1996, 39, 4340-4344.
64. (a) Rosowsky, A.; Forsch, R. A.; Moran, R. G.; Freisheim, J. H. Synthesis and in vitro biological evaluation of β,γ-methano analogues of methotrexate and aminopterin. Pteridines 1990, 2, 133-139.
65. (b) Abraham, A.; McGuire, J. J.; Galivan, J.; Nimec, Z.; Kisliuk, R. L.; Gaumont, Y.; Nair, M. G. Folate analogues. 34. Synthesis and antitumor activity of nonpolyglutamatable inhibitors of dihydrofolate reductase. J. Med. Chem. 1991, 34, 222-227.
66. McGuire, J. J.; Russell, C. A.; Bolanowska, W. E.; Freitag, C. M.; Jones, C. S.; Kalman, T. I. Biochemical and growth inhibition studies of methotrexate and aminopterin analogues containing a tetrazole ring in place of the γ-carboxyl group. Cancer Res. 1990, 50, 1726-1731.
67. (a) McGuire, J. J.; Hart, B. P.; Haile, W. H.; Rhee, M.; Galivan, J.; Coward, J. K. DL-β,β-Difluoroglutamic acid mediates position-dependent enhancement or termination of pteroylpoyl(γ-glutamate) synthesis catalyzed by folylpolyglutamate synthetase. Arch. Biochem. Biophys. 1995, 321, 319-328.
68. (b) McGuire, J. J.; Haile, W. H.; Licato, N. J.; Bolanowska, W. E.; McGuire, J. J.; Coward, J. K. Synthesis and biological activity of folic acid and methotrexate analogues containing L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid. J. Med. Chem. 1996, 39, 56-65.
69. (b) McGuire, J. J.; Hart, B. P.; Haile, W. H.; Magee, K. J.; Rhee, M.; Bolanowska, W. E.; Russell, C.; Galivan, J.; Paul, B.; Coward, J. K. Biological properties of fluoroglutamate-containing analogues of folates and methotrexate with altered capacities to form poly(γ-glutamate) metabolites. Biochem. Pharmacol. 1996, 52, 1295-1303.
70. (c) Tsukamoto, T.; Kitazume, T.; McGuire, J. J.; Coward, J. K. Synthesis and biological evaluation of DL-4,4-difluoroglutamic acid and DL-γ,γ-difluoromethotrexate. J. Med. Chem. 1996, 39, 66-72.
71. (a) Rosowsky, A.; Forsch, R. Methotrexate analogues. 16. Importance of the side-chain amide carbonyl group as a structural determinant of biological activity. J. Med. Chem. 1982, 25, 1454-1459.
72. (b) Moran, R. G.; Colman, P. D.; Forsch, R. A.; Rosowsky, A. A mechanism for the addition of multiple moles of glutamate by folylpolyglutamate synthetase. J. Med. Chem. 1984, 27, 1263-1267.
73. (c) Rosowsky, A.; Forsch, R. A.; Freisheim, J. H.; Danenberg, P. V.; Moran, R. G.; Wick, M. M. Methotrexate analogues. 29. The effect of γ-aminobutyric acid spacers between the pteroyl and glutamate moieties on enzyme binding and cell growth inhibition. J. Med. Chem. 1986, 29, 1872-1876.
74. (d) Rosowsky, A.; Bader, H.; Forsch, R. A.; Moran, R. G.; Freisheim, J. H. Methotrexate analogues, 31. Meta and ortho isomers of aminopterin, compounds with a double bond in the side chain, and a novel analogue modified at the a-carbon: chemical and in vitro biological studies. J. Med. Chem. 1988, 31, 763-768.
75. Tsukamoto, T.; Haile, W. H.; McGuire, J. J.; Coward, J. K. Mechanism-based inhibition of human folylpolyglutamate synthetase: design, synthesis, and biochemical characterization of a phosphapeptide mimic of the tetrahedral intermediate. Arch. Biochem. Biophys. 1998, 355, 109-118.
76. Marsham, P. R.; Jackman, A. L.; Hayter, A. J.; Daw, M. R.; Snowden, J. L.; O'Connor, B. M.; Bishop, J. A. M.; Calvert, A. H.; Hughes, L. R. Quinazoline antifolate thymidylate synthase inhibitors: bridge modifications and conformationally restricted analogues in the C2-methyl series. J. Med. Chem. 1991, 34, 2209-2218.
77. (a) Duch, D. S.; Banks, S.; Dev, I. K.; Dickerson, S. H.; Ferone, R.; Heath, S. S.; Humphreys, J.; Knick, V.; Pendergast, W.; Singer, S.; Smith, G. K.; Waters, K.; Wilson, H. R. Cancer Res. 1993, 53, 810-818.
78. (b) Pendergast, W.; Dickerson, S. H.; Dev, I. K.; Ferone, R.; Duch, D. S.; Smith, G. K. Benzo[f]quinazoline inhibitors of thymidylate synthase: methyleneamino-linked aroylglutamate derivatives. J. Med. Chem. 1994, 37, 838-844.
79. (c) Hanlon, M. H.; Ferone, R. In vitro uptake, anabolism, and cellular retention of 1843U89 and other benzoquinazoline inhibitors of thymidylate synthase. Cancer Res. 1996, 56, 3301-3306.
80. (a) Taylor, E. C.; Zhou, P.; Jennings, L. D.; Mao, Z.; Hu, B.; Jun, J.-G. Novel synthesis of a conformationally constrained analogue of DDATHF. Tetrahedron Lett. 1997, 38, 521-524.
81. (b) Taylor, E. C.; Jennings, L. D.; Mao, Z.; Hu, B.; Jun, J.-G.; Zhou, P. Synthesis of conformationally constrained glutamate analogues of the antitumor agents DDATHF, LY254155, and LY231514. J. Org. Chem. 1997, 62, 5392-5403.
82. Peltier, D. Interaction of substituents in the benzene ring. Substituted o-toluic acids and their esters. Bull. Soc. Sci. Bretagne 1956, 31, 7-92; Chem. Abstr. 1958, 52, 9016h.
83. Peltier, D. Interaction of substituents in the benzene ring. Substituted o-toluic acids and their esters. Bull. Soc. Sci. Bretagne 1956, 31, 7-92; Chem. Abstr. 1958, 52, 9016h.
84. Moran, R. G.; Colman, P. D. Mammalian folyl polyglutamate synthetase: partial purification and properties of the mouse liver enzyme. Biochemistry 1984, 23, 4580-4589.
85. (a) Sanghani, P.; Sanghani, S.; Freemantle, S. J.; Taylor, S. M.; Moran, R. G. Eukaryotic expression of human folylpoly-γ-glutamate synthetase. AACR Proc. 1995, 36, 379.
86. (b) Freemantle, S. J.; Taylor, S. M.; Krystal, G.; Moran, R. G. Upstream organization of and multiple transcripts from the human folylpoly-γ-glutamate sythetase gene. J. Biol. Chem. 1995, 270, 9579-9584.
87. (c) Taylor, S. M.; Freemantle, S. J.; Moran, R. G. Structural organization of the human folylpoly-γ-glutamate synthetase gene: evidence for a sigle genomic locus. Cancer Res. 1995, 55, 6030-6034.
88. The human enzyme has also been expresssed in bacteria: (a) Garrow, T. A.; Admon, A.; Shane, B. Expression cloning of a human cDNA encoding folylpoly(γ-glutamate) synthetase and determination of its primary structure. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9151-9155.
89. (b) Chen, L.; Qi, H.; Korenberg, J.; Garrow, T. A.; Choi, Y.-J.; Shane, B. Purification and properties of human cytosolic folylpoly-γ-glutamate synthetase and organization, localization, and differential splicing of its gene. J. Biol. Chem. 1998, 271, 13077-13087.
90. Antonsson, B.; Barredo, J.; Moran, R. G. A microassay for mammalian folypolyglutamate synthetase. Anal. Biochem. 1990, 186, 8-13.
91. Moran, R. G.; Spears, C. P.; Heidelberger, C. Biochemical determinants of tumor sensitivity to 5-fluorouracil: ultrasensitive methods for determination of 5-fluoro-2′-deoxyuridylate, 2′-deoxyuridylate, and thymidylate synthetase. Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 1456-1460.
92. 16d,e Thus the likelihood of widely divergent biochemical and biological activities for the individual diastereomers of 2 and 4 seems remote.
93. Barnett, C. J.; Wilson, T. M.; Wendel, S. R.; Winningham, M. J.; Deeter, J. B. Asymmetric synthesis of lometrexol ((6R)-5, 10-dideaza-5,6,7,8-tetrahydrofolic acid). J. Org. Chem. 1994, 59, 7038-7045; see also earlier reference cited.
94. Pizzorno, G.; Sokoloski, J. A.; Cashmore, A. R.; Moroson, B. A.; Cross, A. D.; Beardsley, G. P. Intracellular metabolism of 5,10-dideazatetrahydrofolic acid in human leukemic cell lines. Mol. Pharmacol. 1991, 39, 85-89.
95. Shih, C.; Chen, V. J.; Gossett, L. S.; Gates, S. B.; MacKellar, W. C.; Habeck, L. L.; Shackelford, K. A.; Mendelsohn, L. G.; Soose, D. J.; Patel, V. F.; Andis, L. L.; Bewley, J. R.; Rayl, E. A.; Moroson, B. A.; Beardsley, G. P.; Kohler, W.; Ratnam, M.; Schultz, R. M. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997, 57, 1116-1123.
96. Sun, X.; Bognar, A. L.; Baker, E. N.; Smith, C. A. Structural homologies with ATP-and folate-binding enzymes in the crystal structure of folylpolyglutamate synthetase. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 6647-6652.
97. Banerjee, R. V.; Shane, B.; McGuire, J. J.; Coward, J. K. Dihydrofolate synthetase and folylpolyglutamate synthetase: direct evidence for intervention of acyl phosphate intermediates. Biochemistry 1988, 27, 9062-9070.
98. Taylor, E. C.; Tseng, C.-P.; Harrington, P. J.; Beardsley, G. P.; Rosowsky, A.; Wick, M. Synthesis and biological activity of 5-deazafolic acid and 5-deazaaminopterin. In Chemistry and Biology of Pteridines; Blair, J. A., Ed.; Walter de Gruyter: Berlin, 1983; pp 115-119.
99. Sanghani, S.; Moran, R. G. Tight binding of folate substrates and inhibitors to recombinant mouse glycinamide ribonucleotide formyltransferase. Biochemistry 1997, 36, 10506-10516. 38