The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents

Journal of Medicinal Chemistry

Volumn 51, Issue 15, 2008, Pages 4589-4600

  Gangjee, Aleem ^a   Jain, Hiteshkumar D ^a,d   Queener, Sherry F ^b   Kisliuk, Roy L ^c  

^a DUQUESNE UNIVERSITY   (United States)

^b INDIANA UNIVERSITY   (United States)

^c TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF WISCONSIN MILWAUKEE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 HYDROXY 2 PENTASONE; 1 HYDROXY 3 METHYL 2 BUTANONE; 2 AMINO 4 PROPYL FURAN 3 CARBONITRILE; 2 HYDROXYACID; 2,4 DIAMINO 5 ISOPROPYL 6 (2',6' DICHLOROPHENYLSULFANYL) 7H PRYRROL0[2,3 D]PYRIMIDINE; 2,4 DIAMINO 5 ISOPROPYL 7H PYRROLO[2,3 D]PRYIMIDINE; 2,4 DIAMINO 5 PROPYL 6 (1' NAPTHYLSULFANYL) 7H PYRROLO[2,3 D]PYRIMIDINE; 2,4 DIAMINO 5 PROPYL 6 (2',6' DICHLOROPHENYLSULFANYL) 7H PRYRROL0[2,3 D]PYRIMIDINE; 2,4 DIAMINO 5 PROPYL 7H PYRROLO[2,3 D]PRYIMIDINE; [4 [(2,4 DIAMINO 5 ISOPROPYL 7H PYRROLO[2,3 D]PRYIMIDIN 6 YL)SULFANYL] BENZOYL] GLUTAMIC ACID; [4 [(2,4 DIAMINO 5 PROPYL 7H PYRROLO[2,3 D]PRYIMIDIN 6 YL)SULFANYL] BENZOYL] GLUTAMIC ACID; [4 [(2,4 DIAMINO 5 PROPYL 7H PYRROLO[2,3 D]PRYIMIDIN 6 YL)SULFANYL]BENZOIC ACID; [4 [(2,4 DIAMINO 5 PROPYL 7H PYRROLO[2,3 D]PRYIMIDIN 6 YL)SULFANYL]BENZYL]GLUTAMATE; ANTIINFECTIVE AGENT; ANTINEOPLASTIC AGENT; DIHYDROFOLATE REDUCTASE INHIBITOR; ETHYL 4 [2,4 DIAMINO 5 PROPYL 7H PYRROLO[2,3 D]SULFANYL]BENZOATE; FOLIC ACID ANTAGONIST; FURAN; GLUTAMIC ACID DIETHYL ESTER; MALONONITRILE; METHOTREXATE; PEMETREXED; PYRIMETHAMINE; PYRIMIDINE DERIVATIVE; PYRROLO[2,3 D]PYRIMIDINE; RALTITREXED; TRIMETHOPRIM; TRIMETREXATE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ADDITION REACTION; ARTICLE; BIOLOGICAL ACTIVITY; CANCER CELL CULTURE; CHEMICAL MODIFICATION; DRUG INHIBITION; HUMAN; IC 50; NONHUMAN; OXIDATION; SAPONIFICATION; TOXOPLASMA GONDII;

ALKYLATION; ANTI-INFECTIVE AGENTS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; CELL SURVIVAL; FOLIC ACID ANTAGONISTS; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PYRIMIDINES; PYRROLES; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAHYDROFOLATE DEHYDROGENASE;

EID: 49449085415     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800244v     Document Type: Article

References (29)

1. Schnell, J. R.; Dyson, H. J.; Wright, P. E. Structure, Dynamics, and Catalytic Function of Dihydrofolate Reductase. Annu. Rev. Biophys. Biomol. Struct. 2004, 33, 119-140.
2. Willemot, P.; Klein, M. B. Prevention of HIV-associated Opportunistic Infections and Diseases in the Age of Highly Active Antiretroviral Therapy. Expert Rev. Anti-Infect. Ther. 2004, 2, 521-532.
3. Klepser, M. E.; Klepser, T. B. Drug Treatment of HIV-related Opportunistic Infections. Drugs 1997, 53, 40-73.
4. Takimoto, C. H. Antifolates in Clinical Development. Semin. Oncol. 1997, 24, S18-40-S18-51.
5. Bertino, J. R.; Kamen, B.; Romanini, A. Folate Antagonists. In Cancer Medicine; Holland, J. F., Frei, E., Bast, R. C., Kufe, D. W., Morton, D. L., Weichselbaum, R. R., Eds.; Williams & Wilkins: Baltimore, MD, 1997; Vol. 1, pp 907-921..
6. 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 Tumour Cell Growth in Vitro and in Vivo: A New Agent for Clinical Study. Cancer Res. 1991, 51, 5579-5586.
7. Taylor, E. C.; Kuhnt, D.; Shih, C.; Rinzel, S. M.; Grindey, G. B.; Barredo, J.; Jannatipour, M.; Moran, R. A Dideazatetrahydrofolate Analogue Lacking a Chiral Center at C-6, N-[4-[2-(2-Amino-3,4-dihydro-4-oxo-7H- pyrrolo[2,3-d]pyrimidin-5-yl)ethylbenzoyl]-L-glutamic Acid, Is an Inhibitor of Thymidylate Synthase. J. Med. Chem. 1992, 35, 4450-4454.
8. Podzamczer, D.; Salazar, A.; Jimenez, J.; Consiglio, E.; Santin, M.; Casanova, A.; Rufi, G.; Gudiol, F. Intermittent Trimethoprim-Sulfamethoxazole compared with Dapsone-Pyrimethamine for the Simultaneous Primary Prophylaxis of Pneumocystis Pneumonia and Toxoplasmosis in Patients Infected with HIV. Ann. Intern. Med. 1995, 122, 755-761.
9. Roudier, C.; Caumes, E.; Rogeaux, O.; Bricaire, F.; Gentilini, M. Adverse Cutaneous Reactions to Trimethoprim-Sulfamethoxazole in Patients with the Acquired Immunodeficiency Syndrome and Pneumocystis carinii Pneumonia. Arch. Dermatol. 1994, 130, 1383-1386.
10. News. FDA Approve Trimetrexate as Second line Therapy of Pneumocystis carinii Pneumonia. Am. J. Hosp. Pharm. 1994, 51, 591-591.
11. Gangjee, A.; Lin, X.; Kisliuk, R. L.; McGuire, J. J. Synthesis of N-{4-[(2,4-Diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d] pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid and N-{4-[(2-Amino- 4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio] benzoyl}-L-glutamic Acid as Dual Inhibitors of Dihydrofolate Reductase and Thymidylate Synthase and as Potential Antitumor Agents. J. Med. Chem. 2005, 48, 7215-7222.
12. Tripos Inc., 1699 South Hanley Road, St. Louis, MO, 63144.
13. Gangjee, A.; Zeng, Y.; Talreja, T.; McGuire, J. J.; Kisliuk, R. L.; Queener, S. F. Design and Synthesis of Classical and Nonclassical 6-Arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as Antifolates. J. Med. Chem. 2007, 50, 3046-3053.
14. Gangjee, A.; Lin, X.; Queener, S. F. Design, Synthesis, and Biological Evaluation of 2,4-Diamino-5-methyl-6-substituted-pyrrolo[2,3-d] pyrimidines as Dihydrofolate Reductase Inhibitors. J. Med. Chem. 2004, 47, 3689-3692.
15. Cody, V.; Wojtczak, A.; Kaiman, T. I.; Friesheim, J. H.; Blakley, R. L. Conformational Analysis of Human Dihydrofolate Reductase Inhibitor Complexes: Crystal Structure Determination of Wild Type and F31 Mutant Binary and Ternary Inhibitor Complexes. Adv. Exp. Med. Biol. 1993, 338, 481-486.
16. Champness, J. N.; Achari, A.; Ballantine, S. P.; Bryant, P. K.; Delves, C. J.; Stammers, D. K. The Structure of Pneumocystis carinii Dihydrofolate Reductase to 1.9 Å Resolution. Structure 1994, 2, 915-924.
17. Roos, D. S. Primary Structure of the Dihydrofolate Reductase - Thymidylate Synthase Gene from Toxoplasma gondii. J. Biol. Chem. 1993, 268, 6269-6280.
18. Ginkel, S. Z.; Dooley, T. P.; Suling, W. J.; Barrow, W. W. Identification and Cloning of the Mycobacterium avium FolA Gene, Required for Dihydrofolate Reductase Activity. FEMS Microbiol. Lett. 1997, 156, 69-78.
19. Rosowsky, A.; Mota, C. E.; Wright, J. E.; Freisheim, J. H.; Huesner, J. J.; McCormack, J. J.; Queener, S. F. 2,4-Diaminothieno[2,3-d]pyrimidine. Analogs of Trimetrexate and Piritrexim as Potential Inhibitors of Pneumocystis carinii and Toxoplasma gondii Dihydrofolate Reductase. J. Med. Chem. 1993, 36, 3103-3112.
20. Taylor, E. C.; Patel, H. H.; Jun, J.-G. A One-Step Ring Transformation/Ring Annulation Approach to Pyrrolo[2,3-d]pyrimidines. A New Synthesis of the Potent Dihydrofolate Reductase Inhibitor TNP-351. J. Org. Chem. 1995, 60, 6684-6687.
21. Gangjee, A.; Ye, Z.; Queener, S. F. Synthesis of Three Carbon Atom Bridged 2,4-Diaminopyrrolo[2,3-d]pyrimidines as Nonclassical Dihydrofolate Reductase Inhibitors. J. Heterocycl. Chem. 2005, 42, 1127-1133.
22. Rosowsky, A.; Chen, H.; Fu, H.; Queener, S. F. Synthesis of New 2,4-Diaminopyrido[2,3-d]pyrimidine and 2,4-Diaminopyrrolo[2,3-d] pyrimidine Inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium Dihydrofolate Reductase. Bioorg. Med. Chem. 2003, 11, 59-67.
23. Rosowsky, A.; Fu, H.; Queener, S. F. Synthesis of New 2,4-Diamino-7H-pyrrolo[2,3-d]pyrimidines via the Taylor Ring Transformation/Ring Annulation Strategy. J. Heterocycl. Chem. 2001, 38, 1197-1202.
24. Ueno, Y.; Okawara, M. Oxidation Using Distannoxane. I. Selective Oxidation of Alcohols. Tetrahedron Lett. 1976, 50, 4597-4600.
25. Gangjee, A.; Jain, H. D.; McGuire, J. J.; Kisliuk, R. L. Benzoyl Ring Halogenated Classical 2-Amino-6-methyl-3,4-dihydro-4-oxo-5-substituted Thiobenzoyl-7H-pyrrolo[2,3-d]pyrimidine Antifolates as Inhibitors of Thymidylate Synthase and as Antitumor Agents. J. Med. Chem. 2004, 47, 6730-6739.
26. Gangjee, A.; Jain, H. D.; Phan, J.; Lin, X.; Song, X.; McGuire, J. J.; Kisliuk, R. L. Dual Inhibitors of Thymidylate Synthase and Dihydrofolate Reductase as Antitumor Agents: Design, Synthesis, and Biological Evaluation of Classical and Nonclassical Pyrrolo[2,3-d]pyrimidine Antifolates. J. Med. Chem. 2006, 49, 1055-1065.
27. Matsumoto, T.; Ohishi, M.; Inoue, S. Selective Cross-Acyloin Condensation Catalyzed by Thiazolium Salt. Formation of 1-Hydroxy-2-one from Formaldehyde and Other Aldehydes. J. Org. Chem. 1985, 50, 603-606.
28. We thank the Developmental Therapeutics Program of the National Cancer Institute for performing the in vitro anticancer evaluation.
29. Cody, V.; Luft, J. R.; Pangborn, W. Understanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-Type and Leu22Arg Variant Mouse and Human Dihydrofolate Reductase Ternary Crystal Complexes with Methotrexate and NADPH. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2005, 61, 147-155.