Analogues of N(α)-(4-amino-4-deoxypteroyl)-N(δ)-hemiphthaloyl-L- ornithine (PT523) modified in the side chain: Synthesis and biological evaluation

Journal of Medicinal Chemistry

Volumn 40, Issue 3, 1997, Pages 286-299

  Rosowsky, Andre ^a   Vaidya, Chitra M ^a   Bader, Henry ^a   Wright, Joel E ^a   Teicher, Beverly A ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

METHOTREXATE; NALPHA (4 AMINO 4 DEOXYPTEROYL) NDELTA HEMIPHTHALOYLORNITHINE; ORNITHINE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL CULTURE; DRUG EFFECT; DRUG SCREENING; HUMAN; HUMAN CELL; LUNG NON SMALL CELL CANCER; MOUSE; NONHUMAN; SQUAMOUS CELL CARCINOMA;

ANIMALS; ANTINEOPLASTIC AGENTS; CARCINOMA, SQUAMOUS CELL; CELL DIVISION; DRUG SCREENING ASSAYS, ANTITUMOR; FOLIC ACID ANTAGONISTS; GLUTAMATES; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; METHOTREXATE; MICE; MOLECULAR STRUCTURE; ORNITHINE; PTERINS; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAHYDROFOLATE DEHYDROGENASE; TUMOR CELLS, CULTURED;

EID: 0031044977     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9606453     Document Type: Article

References (49)

1. Fabre, I.; Fabre, G.; Goldman, I. D. Polyglutamylation, an important element in methotrexate cytotoxicity and selectivity in tumor versus murine granulocytic progenitor cells in vitro. Cancer Res. 1984, 44, 3190-3195.
2. (a) Samuels, L. L.; Moccio, D. M.; Sirotnak, F. M. Similar differential for total polyglutamylation and cytotoxicity among various folate analogues in human and murine tumor cells in vitro. Cancer Res. 1985, 45, 1488-1495.
3. (b) Rumberger, B. G.; Barrrueco, J. R.; Sirotnak, F. M. Differing specificities for 4-aminofolate analogues of folylpolyglutamate synthetase from tumors and proliferative intestinal epithelium of the mouse and significance for selective antitumor action. Cancer Res. 1990, 50, 4639-4643.
4. Barredo, J.; Moran, R. G. Determinants of antifolate cytotoxicity: folylpolyglutamate synthetase activity during cellular proliferation and development. Mol. Pharmacol. 1992, 42, 687-694.
5. McGuire, J. J.; Bertino, J. R. Enzymatic synthesis and function of folylpolyglutamates. Mol. Cell. Biochem. 1981, 38, 19-48.
6. For papers on the primary sequence, structural organization, and polymorphism of the human FPGS gene, see: (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. (b) Freemantle, S. J.; Taylor, S. M.; Krystal, G.; Moran, R. G. Upstream organization of and multiple transcripts from the human folylpoly-γ-glutamate synthetase gene. J. Biol. Chem. 1995, 270, 9574-9584. (c) Taylor, S. M.; Freemantle, S. J.; Moran R. G. Structural organization of the human folyl-γ-polyglutamate synthetase gene: Evidence for a single genomic locus. Cancer Res. 1995, 55, 6030-6034.
7. For papers on the primary sequence, structural organization, and polymorphism of the human FPGS gene, see: (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. (b) Freemantle, S. J.; Taylor, S. M.; Krystal, G.; Moran, R. G. Upstream organization of and multiple transcripts from the human folylpoly-γ-glutamate synthetase gene. J. Biol. Chem. 1995, 270, 9574-9584. (c) Taylor, S. M.; Freemantle, S. J.; Moran R. G. Structural organization of the human folyl-γ-polyglutamate synthetase gene: Evidence for a single genomic locus. Cancer Res. 1995, 55, 6030-6034.
8. For papers on the primary sequence, structural organization, and polymorphism of the human FPGS gene, see: (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. (b) Freemantle, S. J.; Taylor, S. M.; Krystal, G.; Moran, R. G. Upstream organization of and multiple transcripts from the human folylpoly-γ-glutamate synthetase gene. J. Biol. Chem. 1995, 270, 9574-9584. (c) Taylor, S. M.; Freemantle, S. J.; Moran R. G. Structural organization of the human folyl-γ-polyglutamate synthetase gene: Evidence for a single genomic locus. Cancer Res. 1995, 55, 6030-6034.
9. Taylor, R. T.; Hanna, M. L. Folate dependent enzymes in cultured Chinese hamster cells: folylpolyglutamate synthetase and its absence in mutants auxotrophic for glycine + adenosine + thymidine. Arch. Biochem. Biophys. 1977, 181, 331-344.
10. Kumar, P.; Kisliuk, R. L.; Gaumont, Y.; Freisheim, J. H.; Nair, M. G. Inhibition of human dihydrofolate reductase by antifolyl polyglutamates. Biochem. Pharmacol. 1989, 38, 541-543.
11. Allegra, C. J.; Chabner, B. A.; Drake, J. C.; Lutz, R.; Rodbard, D.; Jolivet, J. Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates. J. Biol. Chem. 1985, 260, 9720-9726.
12. Allegra, C. J.; Drake, J. C.; Jolivet, J.; Chabner, B. A. Inhibition of phosphoribosyl aminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 4881-4885.
13. (a) 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.
14. (b) McCloskey, D. E.; McGuire, J. J.; Russell, C. A.; Rowan, B. G.; Bertino, J. R. Decreased folylpolyglutamate synthetase activity as a mechanism of methotrexate resistance in CCRF-CEM human leukemia sublines. J. Biol. Chem. 1991, 266, 6181-6187.
15. (c) Li, W.-W.; Lin, J. T.; Schweitzer, B. I.; Tong, W. P.; Niedziecki, D.; Bertino, J. R. Intrinsic resistance to methotrexate in human soft tissue sarcoma cell lines. Cancer Res. 1992, 52, 3908-3913.
16. (a) Rumberger, B. R.; 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 deeresed folylpolyglutamate synthetase activity. Cancer Commun. 1990, 2, 305-310.
17. (b) Braakhuis, B. J. M.; Jansen, G.; Noordhuis, P.; Kegel, A.; Peters, G. J. 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.
18. (a) 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.
19. (b) Lu, K.; Yin, M.-B.; McGuire, J. J.; Bonmasssar, E.; Rustum, Y. M. Mechanisms of resistance to N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2- thenoyl-L-glutamic acid (ZD1694), a folate-based thymidylate synthase inhibitor, in the HCT-8 human ileocecal adenocarinoma cell line. Biochem. Pharmacol. 1995, 50, 391-398.
20. (a) 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.
21. (b) Dev, I.; Dallas, W. S.; Ferone, R.; Hanlon, M.; McKee, D. D.; Yates, B. B. Mode of binding of folate analogs to thymidylate synthase. J. Biol. Chem. 1994, 269, 1873-1882.
22. (a) Matherly, L. H.; Angeles, S. M.; McGuire, J. J. 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.
23. (b) Pizzorno, G.; Moroson, B. A.; Cashmore, A. R.; Russello, O.; Mayer, J. R.; Galivan, J.; Bunni, M. A.; Priest, D. G.; Beardsley, G. P. Multifactorial resistance to 5,10-dideazatetrahydrofolic acid in cell lines derived from human lymphoblastic leukemia CCRF-CEM. Cancer Res. 1995, 55, 566-573.
24. Itoh, F.; Russello, O.; Akimoto, H.; Beardley, G. P. Novel pyrrolo-[2,3-d]pyrimidine antifolate TNP-351: Cytotoxic effect on methotrexate-resistant CCEF-CEM cells and inhibition of transformylases of de novo purine biosynthesis. Cancer Chemother. Pharmacol. 1994, 34, 273-279.
25. Schlemmer, S. R.; Sirotnak, F. M. Retentiveness of methotrexate polyglutamates in cultured L1210 cells. Evidence against a role for mediated plasma membrane transport outward. Biochem. Pharmacol. 1993, 45, 1261-1266.
26. (a) Rosowsky, A.; Forsch, R.; Uren, J.; Wick, M.; Kumar, A. A.; Freisheim, J. H. Methotrexate analogues. 20. Replacement of glutamate by long-chain amino diacids: effects of dihydrofolate redutase inhibition, cytotoxicity, and in vivo antitumor activity. J. Med. Chem. 1983, 26, 1719-1724.
27. (b) 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.
28. α-(4-amino-4-deoxypteroyl)-L-ornithine derivatives: synthesis and in vitro antitumor activity. J. Med. Chem. 1988, 31, 1332-1337.
29. δ-hemiphthaloyl-L-ornithine. Pteridines 1989, 1, 91-98.
30. For other early examples of MTX and AMT analogues modified in the γ-region that were synthesized in this context, see: (a) Rosowsky, A.; Freisheim, J. H.; Bader, H.; Forsch, R. A.; Susten, S. S.; Cucchi, C. A.; Frei, E., III. Methotrexate analogues. 25. Chemical and biological studies on the γ-tert-butyl esters of methotrexate and aminopterin. J. Med. Chem. 1985, 28, 660-667. (b) Rosowsky, A.; Bader, H.; Radike-Smith, M.; Cucchi, C. A.; Wick, M. M.; Freisheim, J. H. Methotrexate analogues. 28. Synthesis and biological evaluation of new γ-monoamides of aminopterin and methotrexate. J. Med. Chem. 1986, 29, 1703-1709.
31. For other early examples of MTX and AMT analogues modified in the γ-region that were synthesized in this context, see: (a) Rosowsky, A.; Freisheim, J. H.; Bader, H.; Forsch, R. A.; Susten, S. S.; Cucchi, C. A.; Frei, E., III. Methotrexate analogues. 25. Chemical and biological studies on the γ-tert-butyl esters of methotrexate and aminopterin. J. Med. Chem. 1985, 28, 660-667. (b) Rosowsky, A.; Bader, H.; Radike-Smith, M.; Cucchi, C. A.; Wick, M. M.; Freisheim, J. H. Methotrexate analogues. 28. Synthesis and biological evaluation of new γ-monoamides of aminopterin and methotrexate. J. Med. Chem. 1986, 29, 1703-1709.
32. Klohs, W. D.; Steinkampf, R. W.; Besserer, J. A.; Fry, D. W. Cross resistance of pleiotropically drug resistant P388 leukemia cells to the lipophilic antifolates trimetrexate and BW 301U. Cancer Lett. 1986, 31, 253-260.
33. Assaraf, Y. G.; Molina, A.; Schimke, R. T. Cross-resistance to the lipid-soluble antifolate trimetrexate in human carcinoma cells with the multidrug resistance phenotype. J. Natl. Cancer Inst. 1989, 81, 290-294.
34. Baccanari, D. P.; Tansik, R. L. Multiple drug resistance and the relationship to brain penetration by lipophilic dihydrofolate reductase inhibitors. Proc. Am. Assoc. Cancer Res. 1990, 31, 339.
35. Kuyper, L. F.; Baccanari, D. P.; Jones, M. L.; Hunter, R. N.; Tansik, R. L.; Joyner, J. S.; Boytos, C. M.; Rudolph, S. K.; Knick, V.; Wilson, H. R.; Cadell, J. M.; Friedman, H. S.; Comley, J. C. W.; Stables, J. N. High-affinity inhibitors of dihydrofolate reductases: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with small molecular size. J. Med. Chem. 1996, 39, 892-903.
36. Rhee, M. S.; Galivan, J.; Wright, J. E.; Rosowsky, A. Biochemical studies on PT523, a potent nonpolyglutamatable antifolate, in cultured cells. Mol. Pharmacol. 1994, 45, 783-791.
37. Chen, G.; Wright, J. E.; Rosowsky, A. Dihydrofolate reductase binding and cellular uptake of nonpolyglutamatable antifolates: Correlates of cytotoxicity toward methotrexate sensitive and resistant human head and neck squamous carcinoma cells. Mol. Pharmacol. 1995, 48, 758-765.
38. Westerhof, G. R.; Schornagel, J. H. Kathmann, L.; Jackman, A. L.; Rosowsky, A.; Forsch, R. A.; Hynes, J. B.; Boyle, F. T.; Peters, G. J.; Pinedo, H. M.; 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.
39. Holden, S. A.; Teicher, B. A.; Robinson, M. F.; Northey, D.; Rosowsky, A. Antifolates can potentiate topoisomerase II inhibitors in vitro and in vivo. Cancer Chemother. Pharmacol. 1995, 36, 165-171.
40. ω-hemiphthaloyl-α,ω-diaminoalkanoic acid analogues of aminopterin and 3′,5′-dichloroaminopterin. J. Med. Chem. 1994, 37, 2167-2174.
41. 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. 1986, 29, 655-660.
42. ω-Alkoxycarbonylation of α,ω-diaminoacids with 2-(trimethylsilyl)ethyl 4′-nitrophenylcarbonate. J. Org. Chem. 1983, 48, 1539-1541.
43. Roeder, G. On the condensation of urea with acid esters. Ber. 1913, 46, 2560-2564.
44. Nefkens, G. H. L.; Tesser, G. I.; Nivard, R. J. F. A simple preparation of phthaloyl amino acids via a mild phthaloylation. Rec. Trav. Chim. Pays-Bas 1960, 79, 658-698.
45. 34
46. Cody, V; Luft, J. R.; Ciszak, E.; Kalman, T. I.; Freisheim, J. H. Crystal structure determination at 2,3 Å of recombinant human dihydrofolate reductase ternary complex with NADPH and methotrexate-γ-tetrazole. Anti-Cancer Drug Des. 1992, 7, 483-491.
47. Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A.; Gray-Goodrich, M.; Campbell, H.; Mayo, J.; Boyd, M. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst. 1991, 83, 757-766.
48. Miyajima, K.; Takemoto, M.; Achiwa, K. Prostanoids and related compounds. V. Synthesis of 6-aza-5-oxo-2,3,4-trmor-1,5-inter-m-phenylene prostacyclin derivatives. Chem. Pharm. Bull. 1991, 39, 3175-3179.
49. We are indebted to Dr. J. M. Brown, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, for providing us with the SCC VII tumor used in these experiments. The SCC VII cell line was originally isolated from a spontaneous tumor of the abdominal wall of a C3H mouse by Dr. Herman Suit, Massachusetts General Hospital, Boston, and has been used primarily to study tumor growth delay by chemotherapeutic agents and radiation; cf. Weinberg, M. J.; Rauth, A. M. 5-Fluorouracil infusions and fractionated doses of radiation: studies with a murine squamous cell carcinoma. Int. J. Radiation Oncol. Biol. Phys. 1987, 13, 1691-1699.