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Development of Nonpolyglutamatable DHFR Inhibitors

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Antifolate Drugs in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Inhibitors of the enzyme dihydrofolate reductase (DHFR) first came into use as anti-cancer drugs in 1948 when aminopterin (AMT, 1) and methotrexate (MTX, 2) were found to induce temporary remission in children with acute leukemia (1,2). In the five decades that followed this landmark in the history of chemotherapy (3), the term “an-tifolate” or “antifol” has come to refer not only to inhibitors of DHFR but also to in-hibitors of other enzymes of one-carbon metabolism (4), especially thymidylate synthase (TS) and the two key players of de novo purine biosynthesis, GAR formyl-transferase and AICAR formyltransferase.

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References

  1. Farber S, Diamond LK, Mercer RD, Sylvester RF, Jr., Wolff JA. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 1948;238:787–793.

    Article  PubMed  CAS  Google Scholar 

  2. Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff J, Lenz GG. Effect of chemotherapeutic agents on acute leukemia; folic acid antagonists. Am J Dis Child 1948;78:961–962.

    Google Scholar 

  3. Jukes TH. Searching for magic bullets: early approaches to chemotherapy–antifolates, methotrex-ate–the Bruce F. Cain Memorial Award Lecture. Cancer Res 1987;47:5528–5536.

    PubMed  CAS  Google Scholar 

  4. Kisliuk RL. The biochemistry of folates, In Folate Antagonists as Therapeutic Agents, vol. 1 (Sirot-nak FM, Burchall JJ, Ensminger WD, Montgomery JA, eds.) Academic, New York, 1984, pp. 1–68.

    Google Scholar 

  5. Falco EA, Goodwin LG, Hitchings GH, Rollo IM, Russell PB. 2,4-Diaminopyrimidines–a new se-ries of antimalarials. Br J Pharmacol 1951;6:185–200.

    CAS  Google Scholar 

  6. Hitchings GH, Burchall JJ. Inhibition of folate biosynthesis and function as a basis for chemotherapy. Adv Enzymol 1965;27:417–468.

    PubMed  CAS  Google Scholar 

  7. Werbel LM. Design and synthesis of lipophilic antifols as anticancer agents. Folate Antagonists as Therapeutic Agents, vol. 1. Sirotnak FM, Burchall JJ, Ensminger WD, Montgomery JA, eds. Academic, New York, 1984, pp. 261–287.

    Google Scholar 

  8. Berman EM, Werbel LM. The renewed potential for folate antagonists in contemporary cancer chemotherapy. JMed Chem 1991;34:479–485.

    Article  CAS  Google Scholar 

  9. Roth B, Falco ER, Hitchings GH, Bushby SRM. 5-Benzyl-2,4-diaminopyrimidines as antibacterials agents. I. Synthesis and antibacterial activity in vitro. J Med Pharm Chem 1962;5:1103–1123.

    Article  CAS  Google Scholar 

  10. Werkheiser WC. Specific binding of 4-amino folic acid analogues by folic acid reductase. J Biol Chem 1961;236:888–893.

    CAS  Google Scholar 

  11. Laszlo J, Iland HJ, Sedwick WD. Overcoming methotrexate resistance by a lipophilic antifolate (BW 301U): from theory to models in practice. Adv Enz Regul 1986;24:357–373.

    Article  Google Scholar 

  12. Fry DW, Jackson RC. Biological and biochemical properties of new anticancer folate antagonists. Cancer Metastasis Rev 1987;5:251–270.

    Article  PubMed  CAS  Google Scholar 

  13. Roth B, Cheng CC. Recent progress in the medicinal chemistry of 2,4-diaminopyrimidines. Prog Med Chem 1989;19:269–331.

    Article  Google Scholar 

  14. Goldman ID, Chabner BA, Bertino JR, eds. Folyl and Antifolyl Polyglutamates. Plenum, New York, 1983.

    Google Scholar 

  15. Goldman ID, ed. Proceedings of the Second Workshop on Folyl and Antifolyl Polyglutamates. Praeger, New York, 1985.

    Google Scholar 

  16. Alberto P, Peytreman R, Modenica R, Beretta-Piccoli M. Initial clinical experience with a simultane-ous combination of 2,4-diamino-5-(3’,4’-dichlorophenyl)-6-methylpyrimidine (DDMP) with folinic acid. Cancer Chemother Pharmacol 1978;1:101–105.

    Article  PubMed  CAS  Google Scholar 

  17. Li W-W, Bertino JR. Inability of leucovorin to rescue a naturally methotrexate-resistant human soft tissue sarcoma cell line from trimetrexate cytotoxicity. Cancer Res 1992;52:6866–6870.

    PubMed  CAS  Google Scholar 

  18. Lacerda JF, Goker E, Kherdapour A, Dennig D, Elisseyeff Y, Jagiello C, O’Reilly RJ, Bertino JR. Se-lective treatment of SCID mice bearing methotrexate-transport resistant human acute lymphoblastic leukemia tumors with trimetrexate and leucovorin protection. Blood 1995;85:2675–2679.

    PubMed  CAS  Google Scholar 

  19. Kheradpour A, Berman E, Göker E, Lin JT, Tong WP, Bertino JR. A Phase II study of continuous in-fusion of trimetrexate in patients with refractory acute leukemia. Cancer Investig 1995;13:36–40.

    Article  CAS  Google Scholar 

  20. Galivan J. Transport and metabolism of methotrexate in normal and resistant cultured rat hepatoma cells. Cancer Res 1979;39:735–743.

    PubMed  CAS  Google Scholar 

  21. Rumberger BG, Schmid FA, Otter G, Sirotnak FM. Preferential selection during therapy in vivo by edatrexate compared to methotrexate of resistant L1210 cell variants with decreased folylpolygluta-mate synthetase activity. Cancer Commun 1990;2:305–310.

    PubMed  CAS  Google Scholar 

  22. Roy K, Mitsugi K, Sirlin S, Shane B, Sirotnak FM. Different antifolate-resistant L1210 cell variants with either increased or decreased folylpolyglutamate synthetase gene expression at the level of mRNA transcription. J Biol Chem 1995;270:26918–26922.

    Article  PubMed  CAS  Google Scholar 

  23. Koizumi S. Impairment of methotrexate (MTX)-polyglutamate formation of MTX-resistant K562 cell lines. Gann 1988;79:1230–1237.

    Article  PubMed  CAS  Google Scholar 

  24. Pizzorno G, Mini E, Coronnello M, McGuire JJ, Moroson BA, Cashmore AR, Dreyer RN, Lin JT, Mazzei T, Periti P, Bertino JR. 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.

    PubMed  CAS  Google Scholar 

  25. Whitehead VM, Rosenblatt DS, Vuchich M-J, Suster JJ, Witte A, Beaulieu D. Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lym-phoblastic leukemia: a pilot prognostic factor analysis. Blood 1990;76:44–49.

    PubMed  CAS  Google Scholar 

  26. McCloskey DE, McGuire JJ, Russell CA, Rowan BG, Bertino JR, Pizzorno G, Mini E. Decreased folylpolyglutamate synthetase activity as a mechanism of methotrexate resistance in CCRF-CEM hu-man leukemia sublines. J Biol Chem 1991;266:6181–6187.

    PubMed  CAS  Google Scholar 

  27. Göker E, Lin JT, Trippett T, Elisseyeff Y, Tong WP, Niedzwicki D, Tan C, Steinherz P, Schweitzer BI, Bertino JR. Decreased polyglutamylation of methotrexate in acute lymphoblastic leukemia blasts in adults compared to children with this disease. Leukemia 1993;7:1000–1004.

    PubMed  Google Scholar 

  28. Barredo JC, Synold TW, Laver J, Relling MV, Pui C-H, Priest DG, Evans WE. Differences in consti-tutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia. Blood 1994;84:564–569.

    PubMed  CAS  Google Scholar 

  29. Jolivet J, Schilsky RL, Bailey BD, Drake JC, Chabner BA. Synthesis, retention, and biological activ-ity of methotrexate polyglutamates in cultured human breast cancer cells. J Clin Invest 1982;70:351–360.

    Article  PubMed  CAS  Google Scholar 

  30. Cowan KH, Jolivet J. A methotrexate-resistant human breast cancer cell line with multiple defects, in-cluding diminished formation of methotrexate polyglutamates. J Biol Chem 1984;259:10793–10800.

    PubMed  CAS  Google Scholar 

  31. Frei E III, Rosowsky A, Wright JE, Cucchi CA, Lippke JA, Ervin TJ, Jolivet J, Haseltine WA. De-velopment of methotrexate resistance in a human squamous cell carcinoma of the head and neck in culture. Proc Natl Acad Sci USA 1984;81:2873–2877.

    Article  PubMed  CAS  Google Scholar 

  32. Rosowsky A, Wright JE, Cucchi CA, Lippke JA, Tantravahi R, Ervin TJ, Frei E III. Phenoptyic het-erogeneity in cultured human head and neck squamous cell carcinoma lines with low-level methotrex-ate resistance. Cancer Res 1985;45:6205–6212.

    PubMed  CAS  Google Scholar 

  33. Pizzorno G, Chang Y-M, McGuire JJ, Bertino JR. 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.

    PubMed  CAS  Google Scholar 

  34. Braakhuis BJM, Jansen G, Noordhuis P, Kegel A, Peters GJ. Importance of pharmacodynamics in the in vitro antiproliferative activity of the antifolates methotrexate and 10-ethyl-10-deazaaminopterin against human head and neck squamous cell carcinoma. Biochem Pharmacol 1993;46:2155–2161.

    Article  PubMed  CAS  Google Scholar 

  35. Samuels LL, Feinberg A, Moccio DM, Sirotnak FM, Rosen G. Detection by high-performance liquid chromatography of methotrexate and its metabolites in tumor tissue from osteosarcoma patients treated with high-dose methotrexate/leucovorin rescue. Biochem Pharmacol 1984;33:2711–2714.

    Article  PubMed  CAS  Google Scholar 

  36. Li W-W, Lin JT, Tong WP, Trippett TM, Brennan MF, Bertino JR. Mechanisms of natural resistance to antifolates in human soft tissue sarcomas. Cancer Res 1992;52:1434–1438.

    PubMed  CAS  Google Scholar 

  37. Li W-W, Lin JT, Schweitzer BI, Tong WP, Niedzwicki D, Bertino JR. Intrinsic resistance to methotrexate in human soft tissue sarcoma cell lines. Cancer Res 1992;52:3908–3913.

    PubMed  CAS  Google Scholar 

  38. Curt GA, Jolivet J, Bailey BD, Carney DN, Chabner BA. Synthesis and retention of methotrexate polyglutamates by human small cell lung cancer. Biochem Pharmacol 1984;33:1682–1685.

    Article  PubMed  CAS  Google Scholar 

  39. Curt GA, Jolivet J, Carney DN, Bailey BD, Drake JC, Clendeninn NJ, Chabner BA. Determinants of the sensitivity of human small-cell lung cancer cell lines to methotrexate. J Clin Invest 1985;76:1323–1329.

    Article  PubMed  CAS  Google Scholar 

  40. Barakat RR, Li W-W, Lovelace C, Bertino JR. Intrinsic resistance of cervical squamous cell carci-noma cell lines to methotrexate (MTX) as a result of decreased accumulation of intracellular MTX polyglutamates. Gynecol Oncol 1993;51:54–60.

    Article  PubMed  CAS  Google Scholar 

  41. Rhee MS, Wang Y, Nair MG, Galivan J. Acquisition of resistance to antifolates caused by enhanced y-glutamyl hydrolase activity. Cancer Res 1993;53:2227–2230.

    PubMed  CAS  Google Scholar 

  42. Yao R, Rhee MS, Galivan J. Effects of γ-glutamyl hydrolase on folyl and antifolylpolyglutamates in cultured H35 hepatoma cells. Mol Pharmacol 1995;48:505–511.

    PubMed  CAS  Google Scholar 

  43. Rots MG, Pieters R, Noordhuis P, van Zantwijk CH, Peters GJ, Veerman AJP, Jansen G. Role of folylpolyglutamate synthetase (FPGS) and folylpolyglutamate hydrolase (FPGH) in methotrexate (MTX) polyglutamylation in childhood leukemia. AACR Proc 1997;38:162.

    Google Scholar 

  44. Wright WB Jr, Cosulich DB, Fahrenbach MJ, Waller CW, Smith JM Jr, Hultquist ME. Analogs of pteroylglutamic acid. IV. Replacement of glutamic acid by other amino acids. J Am Chem Soc 1949;71:3014–3017.

    Article  CAS  Google Scholar 

  45. Cosulich DB, Seeger DR, Fahrenbach MJ, Roth B, Mowat JH, Smith JM, Jr, Hultquist ME. Analogs of pteroylglutamic acid. VI. 3’, 5’ -Dihalopteroyl derivatives. JAm Chem Soc 1951;73:2554–2557.

    Article  CAS  Google Scholar 

  46. Suster DC, Tarnauceanu E, Ionescu D, Dobre V, Niculescu-Duvaz I. Potential anticancer agents. 16. Methotrexate analogues with a modified peptide side chain. J Med Chem 1978;21:1162–1165.

    Article  PubMed  CAS  Google Scholar 

  47. Montgomery JA, Piper JR, Elliott RD, Temple C Jr, Roberts EC, Shealy YF. Analogues of methotrex-ate. J Med Chem 1979;22:862–868.

    Article  PubMed  CAS  Google Scholar 

  48. Mao Z, Pan J, Kalman TI. Design and synthesis of histidine analogues of folic acid and methotrexate as potential folylpolyglutamate synthetase inhibitors. J Med Chem 1996;39:4340–4344.

    Article  PubMed  CAS  Google Scholar 

  49. Harvison PJ, Kalman TI. Synthesis and biological activity of novel folic acid analogues: pteroyl-S-alkylhomocysteine sulfoximines. J Med Chem 1992;35:1227–1233.

    Article  PubMed  CAS  Google Scholar 

  50. Mead JAR, Greenberg NH, Schrecker AW, Seeger DR, Tomcufcik AS. The pharmacology and bio-chemical activity of 4-amino-4-deoxy-l0-methylpteroylaspartic acid. Biochem Pharmacol 1965;14:105–114.

    Article  PubMed  CAS  Google Scholar 

  51. Davoll J, Johnson AM. Quinazoline analogues of folic acid. J Chem Soc (C) 1970;997–1002.

    Google Scholar 

  52. Moran RG, Colman PD, Rosowsky A, Forsch RA, Chan KK. Structural features of 4-amino antifo-lates required for substrate activity with mammalian folylpolyglutamate synthetase. Mol Pharmacol 1985;27:156–166.

    PubMed  CAS  Google Scholar 

  53. Hutchison DJ. Quinazoline antifolates: biologic activities. Cancer Chemother Repts Part1 1968;52:697–705.

    CAS  Google Scholar 

  54. Hutchison DJ, Shimoyama M, Schmid F. Quinazoline antifolates: dosage schedules and toxicity. Can-cer Chemother Repts Part1 1971;55:123–132.

    CAS  Google Scholar 

  55. Carlin SC, Rosenberg RN, Vande Venter L, Friedkin M. Quinazoline antifolates as inhibitors of growth, dihydrofolate reductase, and thymidylate synthase of mouse neuroblastoma cells in culture. Mol Pharmacol 1974;10:194–203.

    PubMed  CAS  Google Scholar 

  56. Hynes JB, Eason DE, Garrett CM, Colven PL Jr, Shores KE, Freisheim JH. Quinazolines as inhibitors of dihydrofolate reductase. 4. Classical analogues of folic and isofolic acid. J Med Chem 1977;20:588–591.

    Article  PubMed  CAS  Google Scholar 

  57. Albrecht AM, Biedler JL, Hutchison DJ. Two different species of dihydrofolate reductase in mam-malian cells differentially resistant to amethopterin and methasquin. Cancer Res 1972;32:1539–1546.

    PubMed  CAS  Google Scholar 

  58. Kumar P, Kisliuk RL, Gaumont Y, Nair MG, Baugh CM, Kaufman BT. Interaction of polyglutamyl derivatives of methotrexate, 10-deazaaminopterin, and dihydrofolate with dihydrofolate reductase. Cancer Res 1986;46:5020–5023.

    PubMed  Google Scholar 

  59. Kumar P, Kisliuk RL, Gaumont Y, Freisheim JH, Nair MG. Inhibition of human dihydrofolate reduc-tase by antifolyl polyglutamates. Biochem Pharmacol 1989;38:541–543.

    Article  PubMed  CAS  Google Scholar 

  60. Sirotnak FM, Donsbach RC. Comparative studies on the transport of aminopterin, methotrexate, and methasquin by the L1210 leukemia cell. Cancer Res 1972;32:2120–2126.

    PubMed  CAS  Google Scholar 

  61. Sirotnak FM, Donsbach RC. Stereochemical characteristics of the folate-antifolate transport mecha-nism in L1210 leukemia cells. Cancer Res 1974;34:371–377.

    PubMed  CAS  Google Scholar 

  62. Sirotnak FM, Donsbach RC. Further evidence for a basis of selective activity and relative responsive-ness during antifolate therapy of murine tumors. Cancer Res 1975;35:1737–1744.

    PubMed  CAS  Google Scholar 

  63. Philips FS, Sirotnak FM, Sodergren JE, Hutchison DJ. Uptake of methotrexate, aminopterin, and methasquin and inhibition of dihydrofolate reductase and of DNA synthesis in mouse small intestine. Cancer Res 1973;33:153–158.

    PubMed  CAS  Google Scholar 

  64. Etcubanas E, Tan C, Go SC, Krakoff IH. Preliminary clinical trials of the quinazoline antifolate methasquin. AACR Proc 1972;13:48.

    Google Scholar 

  65. Rosowsky A, Forsch R, Uren J, Wick M, Kumar AA, Freisheim JH. Methotrexate analogues. 20. Re- placement of glutamate by longer-chain amino diacids: effects on dihydrofolate reductase inhibition, cytotoxicity, and in vivo antitumor activity. J Med Chem 1983;26:1719–1724.

    Article  PubMed  CAS  Google Scholar 

  66. Moran RG, Colman PD, Rosowsky A. Structural requirements for the activity of antifolates as sub-strates for mammalian folylpolyglutamate synthetase. NCI Monogr 1987;5:133–138.

    PubMed  Google Scholar 

  67. Browman GP, Spiegl P, Booker P, Rosowsky A. Comparison of leucovorin protection from a variety of antifolates in human lymphoid cell lines. Cancer Chemother Pharmacol 1985;15:111–114.

    PubMed  CAS  Google Scholar 

  68. Rosowsky A, Bader H, Kohler W, Freisheim JH, Moran RG. Methotrexate analogues. 34. Replace-ment of the glutamate moiety in methotrexate and aminopterin by long-chain 2-aminoalkanedioic acids. J Med Chem 1988;31:1338–1344.

    Article  PubMed  CAS  Google Scholar 

  69. Lee WW, Martinez AP, Goodman L. Folic acid antagonists. Methotrexate analogs containing spuri-ous amino acids. Dichlorohomofolic acid. JMed Chem 1974;17:326–330.

    Article  CAS  Google Scholar 

  70. Rosowsky A, Bader H, Forsch RA, Moran RG, Freisheim JH. 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; cf. erratum in J Med Chem 1989;32:2582.

    Google Scholar 

  71. Matsuoka H, Kato N, Tsuji K, Maruyama N, Suzuki H, Mihara M, Takeda Y, Yano K. Antirheumatic agents. 1. Novel methotrexate derivatives bearing an indoline moiety. Chem Pharm Bull 1996;44:1332–1337.

    Article  PubMed  CAS  Google Scholar 

  72. Matsuoka H, Ohi N, Mihara M, Suzuki H, Miyamoto K, Maruyama N, Tsuji K, Kato N, Akimoto T, Takeda Y, Yano K, Kuroki T. Antirheumatic agents: novel methotrexate derivatives bearing a ben-zoxazine or benzothiazine moiety. J Med Chem 1987;40:105–111.

    Article  Google Scholar 

  73. Galivan J, Inglese J, McGuire JJ, Nimec Z, Coward JK. γ-Fluoromethotrexate: synthesis and biolog-ical activity of a potent inhibitor of dihydrofolate reductase with greatly diminished ability to form poly-γ-glutamates. Proc Natl Acad Sci USA 1985;82:2598–2602.

    Article  PubMed  CAS  Google Scholar 

  74. Hart BP, Haile WH, Licato NJ, Bolanowska WE, McGuire JJ, Coward JK. 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.

    Article  PubMed  CAS  Google Scholar 

  75. Tsushima T, Kawada K, Shiratori O, Uchida N. Fluorine-containing amino acids and their derivatives. 5. Synthesis of novel fluorinated analogues of the antitumor agent, methotrexate. Heterocycles 1985;23:45–49.

    Article  CAS  Google Scholar 

  76. Tsushima T, Kawada K, Ishihara S, Uchida N, Shiratori O, Higaki J, Hirata M. Fluorine-containing amino acids and their derivatives. 7. Synthesis and antitumor activity of a- and γ-substituted methotrexate analogs. Tetrahedron 1988;44:5375–5387.

    Article  CAS  Google Scholar 

  77. McGuire JJ, Graber M, Licato N, Vincenz C, Coward JK, Nimec Z, Galivan J. Biochemical and growth inhibitory effects of the erythro and threo isomers of γ-fluoromethotrexate, a methotrexate analogue defective in polygluatmylation. Cancer Res 1989;49:4517–4525.

    PubMed  CAS  Google Scholar 

  78. Tsukamoto T, Kitazume T, McGuire JJ, and Coward JK. Synthesis and biological evaluation of DL-4,4-difluoroglutamic acid and DL-γ,γ-difluoromethotrexate. J Med Chem 1996;39:66–72.

    Article  PubMed  CAS  Google Scholar 

  79. Licato NJ, Coward JK, Nimec Z, Galivan J, Bolanowska WE, McGuire JJ. Synthesis of N-[N-(4-de-oxy-4-amino-l0-methylpteroyl)-4-fluoroglutamyl]-γ-glutamate , an unusual substrate for folylpoly-γ-glutamate synthetase and γ-glutamyl hydrolase. J Med Chem 1990;33:1022–1027.

    Article  PubMed  CAS  Google Scholar 

  80. McGuire JJ, Hart BP, Haile WH, Magee KJ, Rhee M, Bolanowska WE, Russell C, Galivan J, Paul B, Coward JK. Biological properties of fluoroglutamate-containing analogs of folates and methotrexate with altered capacities to form poly (γ-glutamate) metabolites. Biochem Pharmacol 1996;52:1295–1303.

    Article  PubMed  CAS  Google Scholar 

  81. McGuire JJ, Bolanowska WE, Coward JK, Sherwood RF, Russell CA, Felschow DM. Biochemical and biological properties of methotrexate analogs containing D-glutamic acid or D-erythro,threo-4-fluoroglutamic acid. Biochem Pharmacol 1991;42:2400–2403.

    Article  PubMed  CAS  Google Scholar 

  82. Rosowsky A, Bader H, Freisheim JH. Analogues of methotrexate and aminopterin with γ-methylene and γ-cyano substitution of the glutamate side chain: Synthesis and in vitro biological activity. J Med Chem 1991;34:203–208.

    Article  PubMed  CAS  Google Scholar 

  83. Abraham A, McGuire JJ, Galivan J, Nimec Z, Kisliuk RL, Gaumont Y, Nair MG. Folate analogues. 34. Synthesis and antitumor activity of non-polyglutamatable inhibitors of dihydrofolate reductase. J Med Chem 1991;34:222–227.

    Google Scholar 

  84. Abraham A, Nair MG, McGuire JJ, Galivan J, Kisliuk RL, Vishnuvajjala BR. Antitumor efficacy of classical non-polyglutamatable antifolates that inhibit dihydrofolate reductase. Adv Exptl Biol Med 1993;338:663–667.

    Article  CAS  Google Scholar 

  85. Rosowsky A, Forsch RA, Moran RG, Freisheim JH. Synthesis and in vitro biological evaluation of β,γ-methano analogues of methotrexate and aminopterin. Pteridines 1990;2:133–139.

    Article  Google Scholar 

  86. Rosowsky A, Forsch R, Uren J, Wick M. Methotrexate analogues. 14. New γ-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents. J Med Chem 1981;24:1450–1455.

    Article  PubMed  CAS  Google Scholar 

  87. Rosowsky A, Freisheim JH, Bader H, Forsch RA, Susten SS, Cucchi CA, Frei E III. Methotrexate ana-logues. 25. Chemical and biological studies on the γ-tert-butyl esters of methotrexate and aminopterin. J Med Chem 1985;28:660–667.

    Article  PubMed  CAS  Google Scholar 

  88. Rosowsky A, Beardsley GP, Ensminger WD, Lazarus H, Yu CS. Methotrexate analogs. 11. Unam-biguous chemical synthesis and in vitro biological evaluation of a- and γ-monoesters as potential pro-drugs. J Med Chem 1978;21:380–386.

    Article  PubMed  CAS  Google Scholar 

  89. Rosowsky A, Forsch RA, Yu CS, Lazarus H, Beardsley GP. Methotrexate analogues. 21. Divergent influence of alkyl chain length on the dihydrofolate reductase affinity and cytotoxicity of methotrex-ate monoesters. J Med Chem 1984;27:605–609.

    Article  PubMed  CAS  Google Scholar 

  90. Rosowsky A, Lazarus H, Yuan GC, Beltz WR, Mangini L, Abelson HT, Modest EJ, Frei E III. Effects of methotrexate esters and other lipophilic antifolates on methotrexate-resistant human leukemic lym-phoblasts. Biochem Pharmacol 1980;29:648–652.

    Article  PubMed  CAS  Google Scholar 

  91. Wright JE, Rosowsky A, Waxman DJ, Trites D, Cucchi CA, Flatow J, Frei E III. Metabolism of methotrexate and γ-tert-butyl methotrexate by human leukemic cells in culture and by hepatic alde-hyde oxidase in vitro. Biochem Pharmacol 1987;36:2209–2214.

    Article  PubMed  CAS  Google Scholar 

  92. Wright JE, Rosowsky A, Cucchi CA, Flatow J, Frei E III. Methotrexate and γ-tert-butyl methotrexate transport in CEM and CEM/MTX human leukemic lymphoblasts. Biochem Pharmacol 1993;46:871–876.

    Article  PubMed  CAS  Google Scholar 

  93. Rosowsky A, Forsch RA, Freisheim JH, Moran RG, Wick M. Methotrexate analogues. 19. Replace-ment of the glutamate side chain in classical antifolates by L-homocysteic acid and L-cysteic acid: ef-fect on enzyme inhibition and antitumor activity. JMed Chem 1984;27:600–604.

    Article  CAS  Google Scholar 

  94. Rosowsky A, Moran RG, Forsch R, Colman P, Wick M. Methotrexate analogues. 17. The antitu-mor activity of 4-amino-4-deoxy-N10-methylpteroyl-D,L-homocysteic acid and its dual inhibition of dihydrofolate reductase and folylpolyglutamate synthetase. Biochem Pharmacol 1984;33:155–162.

    Article  PubMed  CAS  Google Scholar 

  95. Rosowsky A, Yu CS, Uren J, Lazarus H, Wick M. Methotrexate analogues. 13. Chemical and phar-macologic studies on amide, hydrazide, and hydroxamic acid derivatives of the glutamate side-chain. J Med Chem 1981;24:559–567.

    Article  PubMed  CAS  Google Scholar 

  96. Rosowsky A, Forsch R, Uren J, Wick M. Methotrexate analogues. 14. Synthesis of new γ-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents. J Med Chem 1981;24:1450–1455.

    Article  PubMed  CAS  Google Scholar 

  97. Piper JR, Montgomery JA, Sirotnak FM, Chello PL. Syntheses of a- and γ-substituted amides, pep-tides, and esters of methotrexate and their evaluation as inhibitors of folate metabolism. J Med Chem 1982;25:182–187.

    Article  PubMed  CAS  Google Scholar 

  98. Antonjuk DJ, Boadle DK, Cheung HTA, Tran TQ. Synthesis of monoamides of methotrexate from L-glutamic acid monoamide t-butyl esters. J Chem Soc Perkin Trans1 1984:1989–2003.

    Article  Google Scholar 

  99. Antonjuk DJ, Birdsall B, Cheung HTA, Clore GM, Feeney J, Gronenborn A, Roberts GCK, Tran TQ. A 1H n.m.r. study of the role of the glutamate moiety in the binding of methotrexate to Lactobacillus casei dihydrofolate reductase. Br J Pharmacol 1984;81:309–315.

    Google Scholar 

  100. Rosowsky A, Bader H, Radike-Smith M, Cucchi CA, Wick MM, Freisheim JH. Methotrexate ana-logues. 28. Synthesis and biological evaluation of new v-monoamides of aminopterin and methotrex-ate. J Med Chem 1986;29:1703–1709.

    Article  PubMed  CAS  Google Scholar 

  101. Rosowsky A, Bader H, Freisheim JH. Synthesis and biological activity of methotrexate analogues with two acid groups and a hydropobic aromatic ring in the side chain. J Med Chem 1991;34:574–579.

    Article  PubMed  CAS  Google Scholar 

  102. Itoh F, Russello O, Akimoto H, Beardsley GP. Novel pyaolo[2,3-d]pyrimidine antifolate TNP-351: cytotoxic effect on methotrexate-resistant CCRF-CEM cells and inhibition of transfonnylases of de novo purine biosynthesis. Cancer Chemother Pharmacol 1994;34:273–279.

    Article  PubMed  CAS  Google Scholar 

  103. Itoh F, Yoshioka Y, Yukishige K, Yoshia S, Wajima M, Ootsu K, Akimoto H. Nonglutamate type pyrrolo[2,3-d]pyrimidine antifolates. II. Synthesis and antitumor activity of N5-substituted glutamine analogs. Chem Pharm Bull (Tokyo) 1996;44:1498–1509.

    Article  CAS  Google Scholar 

  104. Miwa T, Hitaka T, Akimoto H, Nomura H. Novel pyrrolo[2,3-d]pyrimidine antifolates: synthesis and antitumor activities. J Med Chem 1991;34:555–560.

    Article  PubMed  CAS  Google Scholar 

  105. Miwa T, Hitaka T, Akimoto H. A novel synthetic approach to pyrrolo[2,3-d]pyrimidine antifolates. J Org Chem 1993;58:1696–1701.

    Article  CAS  Google Scholar 

  106. Rosowsky A, Bader H, Cucchi CA, Moran RG, Kohler W, Freisheim JH. Methotrexate analogues. 33. Nδ-Acyl-Nα-(4-amino-4-deoxypteroyl)-L-ornithine derivatives: synthesis and in vitro antitumor ac-tivity. J Med Chem 1988;31:1332–1337.

    Article  PubMed  CAS  Google Scholar 

  107. Sirotnak FM, Chello PL, Piper JR, Montgomery JA. Growth inhibitory, transport and biochemical properties of the γ-glutamyl and y-aspartyl peptides of methotrexate in L1210 leukemia cells in vitro. Biochem Pharmacol 1978;27:1821–1825.

    Article  CAS  Google Scholar 

  108. Heath TD, Montgomery JA, Piper JR, Papahadjopoulos D. Antibody-targeted liposomes: increase in specific toxicity of methotrexate-γ-aspartate. Proc Natl Acad Sci USA 1983;80:1377–1381.

    Article  PubMed  CAS  Google Scholar 

  109. Rosowsky A, Moran RG, Forsch RA, Radike-Smith M, Colman PD, Wick MM, Freisheim JH. Methotrexate analogues. 27. Dual inhibition of dihydrofolate reductase and folylpolyglutamate syn-thetase by methotrexate and aminopterin analogues with a v-phosphonate group in the side chain. Biochem Pharmacol 1986;35:3327–3333.

    Google Scholar 

  110. Rosowsky A, Moran RG, Freisheim JH, Bader H, Forsch RA, Solan VC. Synthesis and biologic activity of new side-chain-altered methotrexate and aminopterin analogs with dual inhibitory action against dihydrofolate reductase and folylpolyglutamate synthetase. NCI Monogr 1987;5:145–152.

    Google Scholar 

  111. Clarke L, Rosowsky A, Waxman DJ. Inhibition of human liver folylpolyglutamate synthetase by non-γ-glutamylatable antifolate analogs. Mol Pharmacol 1987;31:122–127.

    PubMed  CAS  Google Scholar 

  112. Rosowsky A, Forsch RA, Moran RG, Kohler W, Freisheim JH. Methotrexate analogues. 32. Chain ex-tension, a-carboxyl deletion, and γ-carboxyl replacement by sulfonate and phosphonate: effect on en-zyme binding and cell growth inhibition. J Med Chem 1988;31:1326–1331.

    Article  PubMed  CAS  Google Scholar 

  113. McGuire JJ, Russell CA, Bolanowska WE, Freitag CM, Jones CS, Kalman TI. 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.

    PubMed  CAS  Google Scholar 

  114. Cody V, Luft JR, Ciszak E, Kalman TI, Freisheim JH. Crystal structure determination at 2.3Å of re-combinant human dihydrofolate reductase ternary complex with NADPH and methotrexate-γ-tetra-zole. Anticancer Drug Design 1992;7:483–491.

    CAS  Google Scholar 

  115. Kempton RJ, Black AM, Anstead GM, Kumar AA, Blankenship DR, Freisheim JH. Lysine and ornithine analogues of methotrexate as inhibitors of dihydrofolate reductase. J Med Chem 1982;25:475–477.

    Article  PubMed  CAS  Google Scholar 

  116. Rosowsky A, Wright JE, Ginty C, Uren J. Methotrexate analogues. 15. A methotrexate analogue de-signed for active-site-directed irreversible inactivation of dihydrofolate reductase. J Med Chem 1982;25:960–964.

    Article  PubMed  CAS  Google Scholar 

  117. Piper JR, McCaleb GS, Montgomery JA, Schmid FA, Sirotnak FM. Synthesis and evaluation as antifolates of MTX analogues derived from 2,ω-diaminoalkanoic acids. J Med Chem 1985;28:1016–1025.

    Article  PubMed  CAS  Google Scholar 

  118. Rosowsky A, Freisheim JH, Moran RG, Solan VC, Bader H, Wright JE, Radike-Smith M. Methotrex-ate analogues. 26. Inhibition of dihydrofolate reductase and folylpolyglutamate synthetase activity and in vitro cell growth by methotrexate and aminopterin analogues containing a basic amino acid side-chain. J Med Chem 1986;29:655–660.

    Google Scholar 

  119. McGuire JJ, Hsieh P, Franco CT, Piper JR. Folylpolyglutamate synthetase inhibition and cytotoxic ef-fects of methotrexate analogs containing 2,w-diaminoalkanoic acids. Biochem Pharmacol 1986;35:2607–2613.

    Article  PubMed  CAS  Google Scholar 

  120. McGuire JJ, Piper JR, Coward JK, Galivan J. Folate analog nonsubstrates and inhibitors of folylpolyg-lutamate synthetase as potential cancer chemotherapy drugs. NCI Monogr 1987;5:139–144.

    PubMed  Google Scholar 

  121. McGuire JJ, Bolanowska WE, Piper JR. Structural specificity of inhibition of human folylpolygluta-mate synthetase by ornithine-containing analogs. Biochem Pharmacol 1988;37:3931–3939.

    Article  PubMed  CAS  Google Scholar 

  122. Patil SA, Shane B, Freisheim JH, Singh SK, Hynes JB. Inhibition of mammalian folylpolyglutamate synthetase and human dihydrofolate reductase by 5,8-dideaza analogues of folic acid and aminopterin bearing a terminal L-omithine. J Med Chem 1989;32:1559–1565.

    Article  PubMed  CAS  Google Scholar 

  123. Rosowsky A, Forsch RA, Bader H, Freisheim JH. 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.

    Article  PubMed  CAS  Google Scholar 

  124. Rosowsky A, Forsch RA, Moran RG. Inhibition of folylpolyglutamate synthetase by substrate ana-logues with an ornithine side chain. J Heterocycl Chem 1996;33:1355–1361.

    Article  CAS  Google Scholar 

  125. Tsukamoto T, Haile WH, McGuire JJ, Coward JK. Synthesis and biological evaluation of Nα-(4-amino-4-deoxy-10-methylpteroyl)-DL-4,4-difluoroornithine . J Med Chem 1996;39:2536–2540.

    Article  PubMed  CAS  Google Scholar 

  126. Rosowsky A, Wright JE, Shapiro H, Beardsley GP, Lazarus H. A new fluorescent dihydrofolate re-ductase probe for studies of methotrexate resistance. J Biol Chem 1982;257:14162–14167.

    PubMed  CAS  Google Scholar 

  127. Kumar AA, Freisheim JH, Kempton RJ, Anstead GM, Black AM, Judge L. Synthesis and characteri-zation of a fluorescent analogue of methotrexate. J Med Chem 1983;26:111–113.

    Article  PubMed  CAS  Google Scholar 

  128. Rosowsky A, Wright JE, Cucchi CA, Boeheim K, Frei E III. Transport of a fluorescent antifolate by methotrexate-sensitive and methotrexate-resistant human leukemic lymphoblasts. Biochem Pharma-col 1986;35:356–360.

    Article  CAS  Google Scholar 

  129. Rosowsky A, Solan VC, Forsch RA, Delcamp TJ, Baccanari DP, Freisheim JH. Methotrexate ana-logues. 30. Dihydrofolate reductase inhibition and in vitro tumor cell growth inhibition by N-haloacetyl-L-lysine and Ns-haloacetyl-L-ornithine analogues and an acivicin analogue of methotrexate. J Med Chem 1987;30:1463–1469.

    Article  PubMed  CAS  Google Scholar 

  130. Rosowsky A, Bader H, Forsch RA. Synthesis of the folylpolyglutamate synthetase inhibitor Nα-pteroyl-L-ornithine and its Nδ-benzoyl and Ns-hemiphthaloyl derivatives, and an improved synthesis of Nα-(4-amino-4-deoxypteroyl)-N8-hemiphthaloyl-L-omithine. Pteridines 1989;1:91–98.

    Article  CAS  Google Scholar 

  131. Peters GJ, Braakhuis BJM, Rosowsky A, Rots M, Pieters R, van der Wilt CL, Smid K, Jansen G. Pre-clinical activity of PT523 in relation to membrane transport in Eleventh International Symposium on Chemistry and Biology of Pteridines, Berchtesgaden, Germany, June 15–20, 1997, pp. 267–270.

    Google Scholar 

  132. Rosowsky A, Bader H, Wright JE, Keyomarsi K, Matherly LH. Synthesis and biological activity of Nω-hemiphthaloyl-a,w-diaminoalkanoic acid analogues of aminopterin and 3’,5’-dichloro-aminopterin. J Med Chem 1994;37:2167–2174.

    Article  PubMed  CAS  Google Scholar 

  133. Westerhof GR, Schomagel JH, Kathmann I, Jackman AL, Rosowsky A, Forsch RA, Hynes JB, Boyle FT, Peters GJ, Pinedo HM, Jansen G. Carrier- and receptor-mediated transport of folate antagonists targeting folate dependent enzymes: correlates of molecular structure and biological activity. Mol Pharmacol 1995;48:459–471.

    PubMed  CAS  Google Scholar 

  134. Matherly LH, Angeles SM, McGuire JJ. Determinants of the disparate antitumor activities of (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate and methotrexate toward human lymphoblastic leukemia cells, characterized by severely impaired antifolate membrane transport. Biochem Pharmacol 1993;46:2185–2195.

    Article  PubMed  CAS  Google Scholar 

  135. Rosowsky A, Bader H, Frei E III. In vitro and in vivo antitumor activity of Nα-(4-amino-4-de-oxypteroyl)-N-hemiphthaloyl-L-or nithine (PT523), a potent side chain modified aminopterin analog that cannot form polyglutamates. AACR Proc 1991;32:325.

    Google Scholar 

  136. Rosowsky A, Vaidya CM, Bader H, Wright JE, Teicher BA. Analogues of Nα-(4-amino-4-de-oxypteroyl)-Ns-hemiphthaloyl-L-ornithine (PT523) modified in the side chain: synthesis and biolog-ical evaluation. J Med Chem 1997;40:286–299.

    Google Scholar 

  137. Holden SA, Teicher BA, Robinson MF, Northey D, Rosowsky A. Antifolates can potentiate topoiso-merase II inhibitors in vitro and in vivo. Cancer Chemother Pharmacol 1995;36:165–171.

    Article  PubMed  CAS  Google Scholar 

  138. Rhee MS, Galivan J, Wright JE, Rosowsky A. Biochemical studies on PT523, a potent nonpolyglu-tamable antifolate, in cultured cells. Mol Pharmacol 1994;45:783–791.

    PubMed  CAS  Google Scholar 

  139. Wright JE, Pardo AM, Trites DH, Menon K, Rosowsky A. Pharmacokinetics and antifolate activity of Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-L-ornithine (PT523) in SCC VII murine squamous cell carcinoma. AACR Proc 1993;34:277.

    Google Scholar 

  140. Lorico A, Toffoli G, Boiocchi M, Erba E, Broggini M, Rappa G, D’Incalci M. Accumulation of DNA strand breaks in cells exposed to methotrexate or N10-propargyl-5,8-dideazafolic acid. Cancer Res 1988;48:2036–2041.

    Google Scholar 

  141. Fry DW. Cytotoxic synergism between trimetrexate and etoposide: evidence that trimetrexate poten-tiates etoposide-induced protein-associated DNA strand breaks in L1210 cells through intracellular ATP concentrations. Biochem Pharmacol 1990;40:1981–1988.

    Article  PubMed  CAS  Google Scholar 

  142. Rosowsky A, Bader H, Chen Y-N, Forsch RA, Mota CE, Pardo J, Teicher BA, Tretyakov A, Vaidya CM, Wright JE. Potent DHFR inhibition and cytotoxicity of nonpolyglutamatable analogs of aminopterin (AMT). AACR Proc 1997;38:99.

    Google Scholar 

  143. Johnson JM, Meiering EM, Wright JE, Pardo J, Rosowsky A, Wagner G. NMR solution structure of the antitumor compound PT523 and NADPH in the ternary complex with human dihydrofolate re-ductase. Biochemistry 1997;36:4399–4411.

    Article  PubMed  CAS  Google Scholar 

  144. Jackson RC, Hart LI, Harrap KR. Intrinsic resistance to methotrexate of cultured mammalian cells in relation to the inhibition kinetics of their dihydrofolate reductases. Cancer Res 1976;36:1991–1997.

    PubMed  CAS  Google Scholar 

  145. Appleman JR, Prendergast N, Delcamp TJ, Freisheim JH, Blakley RL. Kinetics of the formation and isomerization of methotrexate complexes of recombinant human dihydrofolate reductase. JBiol Chem 1988;263:10304–10313.

    CAS  Google Scholar 

  146. Margosiak SA, Appleman JR, Santi DV, Blakley RL. Dihydrofolate reductase from the pathogenic fungus Pneumocystis carinii: catalytic properties and interaction with antifolates. Arch Biochem Bio-phys 1993;305:499–508.

    Article  CAS  Google Scholar 

  147. Sirotnak FM, Chello PL, DeGraw JI, Piper JR, Montgomery JA. Membrane transport and the molecule basis for selective antitumor action of folate analogs. In: Molecular Actions and Targets for Cancer Chemotherapeutic Agents (Sartorelli AC, Lazo JS, Bertino JR, eds.). Academic, New York, 1981, pp. 349–384.

    Google Scholar 

  148. Chen G, Wright JE, Rosowsky A. Dihydrofolate reductase binding and cellular uptake of nonpolyg-lutamatable antifolates: correlates of cytotoxicity toward methotrexate sensitive and resistant human head and neck squamous carcinoma cells. Mol Pharmacol 1995;48:758–765.

    PubMed  CAS  Google Scholar 

  149. Jackman AL, Taylor GA, Gibson W, Kimbell R, Brown M, Calvert AH, Judson IR, Hughes LR. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tu-mor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res 1991;51:5579–5586.

    PubMed  CAS  Google Scholar 

  150. Schultz RM, Andis SL, Shackelford KA, Gates SB, Ratnam M, Mendelsohn LG, Shih C; Grindey GB. Role of membrane-associated folate binding protein in the cytotoxicity of antifolates in KB, IGROV1, and L1210A cells. Oncol Res 1995;7:97–102.

    PubMed  CAS  Google Scholar 

  151. Alati T, Worzalla JF, Shih C, Bewley JR, Lewis S, Moran RG, Grindey GB. Augmentation of the ther-apeutic activity of lometrexol [(6-R)5,10-dideazatetrahydrofolate] by oral folic acid. Cancer Res 1996;56:2331–2335.

    PubMed  CAS  Google Scholar 

  152. Duch DS, Banks S, Dev IK, Dickerson SH, Ferone R, Heath LS, Humphreys J, Knick B, Pendergast W, Singer S, Smith GK, Waters K, Wilson HR. Biochemical and cellular pharmacology of 1843U89, a novel benzoquinazoline inhibitor of thymidylate synthase. Cancer Res 1993;53:810–818.

    PubMed  CAS  Google Scholar 

  153. Cody V, Galitsky N, Luft JR, Cotter D, Pangbom, Rosowsky A, Blakley RL. Structure of hDHFR ternary complex with the potent inhibitor, PT523. AACR Proc 1997;38:163.

    Google Scholar 

  154. Cody V, Galitsky N, Luft JR, Pangborn W, Blakley RL. Comparison of two independent crystal struc-ture determinations of the antitumor compound PT523 and NADPH as ternary complexes with human dihydrofolate reductase. In: Eleventh International Symposium on Chemistry and Biology of Pteridines and Folates, Berchtesgaden, Germany, June 15–20, 1997, 403–406.

    Google Scholar 

  155. Piper JR, Johnson CA, Maddry JA, Malik ND, McGuire JJ, Otter GM, Sirotnak RM. Studies on ana-logues of classical antifolates bearing the naphthoyl group in place of benzoyl in the side chain. J Med Chem 1993;36:4161–4171.

    Article  PubMed  CAS  Google Scholar 

  156. Rosowsky A, Bader H, Moran RG, Freisheim JH. 6-Aza-5,8,10-trideaza analogues of tetrahydrofolic acid and tetrahydroaminopterin: synthesis and biological studies. J Heterocycl Chem 1989;26:509–516.

    Article  CAS  Google Scholar 

  157. Fry DW, Werbel LM, Hung J, Besserer JA, Boritzki TJ, Leopold WR. In vivo and in vitro evaluation of 5-[4-(substituted ary1)-1-piperazinyl]-6-alky1–2,4-pyrimidine diamines as antitumor agents. AACR Proc 1986;27:253.

    Google Scholar 

  158. Moran RG, Colman PD, Jones TR. Relative substrate activities of structurally related pteridine, quina-zoline, and pyrimidine analogs for mouse liver folylpolyglutamate synthetase. Mol Pharmacol 1989;36:736–743.

    PubMed  CAS  Google Scholar 

  159. Nair MG, Campbell PT, Braverman E, Baugh CM. Synthesis of thioaminopterin: a potent anti-bacte- rial agent. Tetrahedron Lett 1975;2745–2748.

    Google Scholar 

  160. Nair MG, Campbell PT. Folate analogues altered in the C9-N10 bridge region. 10-Oxafolic acid and oxaaminopterin. J Med Chem 1976;19:825–829.

    Article  PubMed  CAS  Google Scholar 

  161. Nair MG, Chen S-Y, Kisliuk RL, Gaumont Y, Strumpf D. Folate analogues altered in the C9-N10 re-gion. 16. Synthesis and antifolate activity of 11-thiohomoaminopterin. JMed Chem 1980;23:899–903.

    Google Scholar 

  162. Nair MG, Bridges TW, Henkel TJ, Kisliuk RL, Gaumont Y, Sirotnak FM. Folate analogues altered in the C9-N10 bridge regions. 18. Synthesis and antitumor evaluation of 1 I-oxahomoaminopterin and re-lated compounds. JMed Chem 1981;24:1068–1073.

    Article  CAS  Google Scholar 

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  1. Andre Rosowsky
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  1. The Cancer Research Campaign Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK

    Ann L. Jackman

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Rosowsky, A. (1999). Development of Nonpolyglutamatable DHFR Inhibitors. In: Jackman, A.L. (eds) Antifolate Drugs in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-725-3_4

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