Ester Soft Drugs
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 15 2401
(26) Bertino, J . R.; Sawacki, W. L.; Moroson, B. A.; Cashmore, A. R.;
Elslager, E. F. 2,4-Diamino-5-methyl-6-[(2,4,5-trimethoxy-
anilino)methyl]quinazoline (TMQ), A Potent Non-Classical Folate
Antagonist Inhibitor-I. Biochem. Pharmacol. 1979, 28, 1983-
1987.
(27) Weir, E. C.; Cashmore, A. R.; Dreyer, R. N.; Graham, M. L.;
Hsiao, N.; Moroson, B. A.; Sawacki, W. L.; Bertino, J . R.
Pharmacology and Toxicity of a Potent “Nonclassical” 2,4-
Diamino Quinazoline Folate Antagonist, Trimetrexate, in Nor-
mal Dogs. Cancer Res. 1982, 42, 1696-1702.
(48) Piper, J . R.; McCaleb, G. S.; Montgomery, J . A.; Kisliuk, R. L.;
Gaumont, Y.; Sirotnak, F. M. Synthesis and Antifolate Activity
of 5-Methyl-5-Deaza-Analogues of Aminopterin. Methotrexate,
Folic Acid, and N-10 Methyl Folic Acid. J . Med. Chem. 1986,
29, 1080-1086.
(49) Gangjee, A.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L.
6-Substituted 2,4-Diamino-5-methylpyrido[2,3-d]pyrimidines as
Inhibitors of Dihydrofolate Reductases from Pneumocystis carinii
and Toxoplasma gondii and as Antitumor Agents. J . Med. Chem.
1995, 38, 1778-1785.
(50) Piper, J . R.; McCaleb, G. S.; Montgomery, J . A.; Kisliuk, R. L.;
Gaumont, Y.; Thorndike, J .; Sirotnak, F. M. Synthesis and
Antifolate Activity of 5-Methyl-5,10-dideaza Analogues of Ami-
nopterin and Folic Acid and an Alternative Synthesis of 5,10-
Dideazatetrahydrofolic Acid, a Potent Inhibitor of Glycinamide
Ribonucleotide Formyltransferase. J . Med. Chem. 1988, 31,
2164-2169.
(51) De Graw, J . I.; Tagawa, H.; Christie, P. H.; Lawson, J . A.; Grown,
E. G.; Kisliuk, R. L.; Gaumont, Y. Synthesis of 5,10-Dideaza-
aminopterin. J . Heterocycl. Chem. 1986, 23, 1-4.
(52) Piper, J . R.; Malik, N. D.; Rhee, M. S.; Galivan, J .; Sirotnak, F.
M. Synthesis and Antifolate Evaluation of the 10-Propargyl
Derivatives of 5-Deazafolic Acid, 5-Deazaaminopterin, and
5-Methyl-5-deazaaminopterin. J . Med. Chem. 1992, 35, 332-
337.
(53) Taylor, E. C. New Pathways from Pteridines. Design and
Synthesis of a New Class of Potent and Selective Antitumor
Agents. J . Heterocycl. Chem. 1990, 27, 1-12.
(54) Piper, J . R.; Montgomery, J . A. Preparation of 6-(Bromomethyl)-
2,4-pteridinediamine Hydrobromide and Its Use in Improved
Syntheses of Methotrexate and Related Compounds. J . Org.
Chem. 1977, 42, 208-211.
(55) Su, T.-L.; Huang, J .-T.; Burchenal, J . H.; Watanabe, K. A.; Fox,
J . J . Synthesis and Biological Activites of 5-Deaza Analogues of
Aminopterin and Folic Acid. J . Med. Chem. 1986, 29, 709-715.
(56) Srinivasan, A.; Broom, A. D. Pyridopyrimidines. 12. Synthesis
of 8-Deaza Analogues of Aminopterin and Folic Acid. J . Org.
Chem. 1981, 46, 1777-1781.
(57) Piper, J . R.; J ohnson, C. A.; Maddry, J . A.; Malik, D. N.; McGuire,
J . J .; Otter, G. M.; Sirotnak, F. M. Studies on Analogues of
Classical Antifolates Bearing the Naphthoyl Group in Place of
the Benzoyl in the Side Chain. J . Med. Chem. 1993, 36, 4161-
4171.
(58) Graffner-Nordberg, M.; Marelius, J .; Ohlsson, S.; Persson, Å.;
Swedberg, G.; Andersson, P.; Andersson, S. E.; Åqvist, J .;
Hallberg, A. Computational Predictions of Binding Affinities to
Dihydrofolate Reductase: Synthesis and Biological Evaluation
of Methotrexate Analogues. J . Med. Chem. 2000, 43, 3852-3861.
(59) Harris, N. V.; Smith, C.; Bowden, K. A Simple Synthesis of
5,8,10-Trideazaminopterin Analogues. Synlett 1990, 577-578.
(60) Harris, N. V.; Smith, C.; Bowden, K. Antifolate and Antibacterial
Activities of 6-Substituted 2,4-Diaminoquinazolines. Eur. J . Med.
Chem. 1992, 27, 7-18.
(61) For a review, see the following. Heck, R. F. Palladium-Catalyzed
Vinylation of Organic Halides. Org. React. 1982, 27, 345-390.
(62) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed Cross-coupling
Reactions; Diedrich, F., Stang, P. J ., Eds.; Wiley-VCH: Wein-
heim, 1998.
(63) For a review, see the following. Beletskaya, I. P.; Cheprakov, A.
V. The Heck Reaction as a Sharpening Stone of Palladium
Catalysis. Chem. Rev. 2000, 100, 3009-3066.
(64) Temple, C., J r.; Elliott, R. D.; Montgomery, J . A. Pyrido[2,3-d]-
pyrimidines. Synthesis of the 5-Deaza Analogues of Aminopterin,
Methotrexate, Folic Acid, and N10-Methylfolic Acid. J . Org.
Chem. 1982, 47, 761-764.
(65) Chio, L.-C.; Queener, S. F. Identification of Highly Potent and
Selective Inhibitors of Toxoplasma gondii Dihydrofolate Reduc-
tase. Antimicrob. Agents Chemother. 1993, 37, 1914-1923.
(66) For a review, see the following. Blaney, J . M.; Hansch, C.; Silipo,
C.; Vittoria, A. Structure-Activity Relationships of Dihydrofolate
Reductase Inhibitors. Chem. Rev. 1984, 84, 333-407.
(67) Gangjee, A.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L. 2,4-
Diamino-5-deaza-6-Substituted Pyrido[2,3-d]pyrimidine Anti-
folates as Potent and Selective Nonclassical Inhibitors of Dihy-
drofolate Reductases. J . Med. Chem. 1996, 39, 1438-1446.
(68) Schornagel, J . H.; Chang, P. K.; Sciarini, L. J .; Moroson, B. A.;
Mini, E.; Cashmore, A. R.; Bertino, J . Synthesis and Evaluation
of 2,4-Diamino Quinazoline Antifolates with Activity against
Methotrexate Resistan Human Tumor Cells. Biochem. Pharma-
col. 1984, 33, 3251-3255.
(69) Hynes, J . B.; Harmon, S. J .; Floyd, G. G.; Farrington, M.; Hart,
L. D.; Gale, G. R.; Washtein, W. L.; Susten, S. S.; Freisheim, J .
H. Chemistry and Antitumor Evaluation of Selected Classical
2,4-Diaminoquinazoline Analogues of Folic Acid. J . Med. Chem.
1985, 28, 209-215.
(70) Hansson, T.; Marelius, J .; Åqvist, J . Ligand Binding Affinity
Prediction by Linear Binding Free Energies. J . Comput. Aided
Mol. Des. 1998, 12, 27-35.
(28) Duch, D. S.; Edelstein, M. P.; Bowers, S. W.; Nichol, C. A.
Biochemical and Chemotherapeutic Studies on 2,4-Diamino-
6-(2,5-dim et h oxyben zyl)-5-m et h ylpyr ido[2,3-d ]pyr im idin e
(BW301U), A Novel Lipid-Soluble Inhibitor of Dihydrofolate
Reductase. Cancer Res. 1982, 42, 3987-3994.
(29) Lin, J . T.; Cashmore, A. R.; Baker, M.; Dreyer, R. N.; Ernstoff,
M.; Marsh, J . C.; Bertino, J . R.; Whitfield, L. R.; Delap, R.; Grillo-
Lopez, A. Phase I Studies with Trimetrexate: Clinical Pharma-
cology, Analytical Methodology, and Pharmacokinetics. Cancer
Res. 1987, 47, 609-616.
(30) Kovacs, J . A.; Allegra, C. A.; Swan, J . C.; Drake, J . C.; Parillo,
J . E.; Chabner, B. A.; Masur, H. Potent Antipneumocystis and
Antitoxoplasma Activities of Piritrexim, a Lipid-Soluble Anti-
folate. Antimicrob. Agents Chemother. 1988, 32, 430-433.
(31) FDA Approves Trimetrexate As A Second Line Therapy For
Pneumocystis carinii Pneumonia. Am. J . Hosp. Pharm. 1994,
51, 591-592.
(32) Allegra, C. J .; Kovacs, J . A.; Drake, J . C.; Swan, J . C.; Chabner,
B. A.; Masur, H. Activity of Antifolates Against Pneumocystis
carinii Dihydrofolate Reductase and Identification of a Potent
New Agent. J . Exp. Med. 1987, 165, 926-931.
(33) Broughton, M. C.; Queener, S. F. Pneumocystis carinii Dihydro-
folate Reductase Used to Screen Potential Antipneumocystis
Drugs. Antimicrob. Agents Chemother. 1991, 35, 1348-1355.
(34) Allegra, C. J .; Chabner, B. A.; Tuazon, C. U.; Ogata-Agakaki,
D.; Baird, B.; Drake, J . C.; Simmons, J . T.; Lack, E. E.;
Shelhamer, J . H.; Balis, F.; Walker, R.; Kovacs, J . A.; Lane, H.
C.; Masur, H. Trimetrexate for the Treatment of Pneumocystis
carinii Pneumonia in Patients with the Acquired Immunodefi-
ceincy Syndrome. N. Engl. J . Med. 1987, 317, 978-985.
(35) Sattler, F. R.; Allegra, C. J .; Verdegem, T. D. Trimetrexate-
Leucoverin Dosage Evaluation Study for the Treatment of
Pneumocystis carinii Pneumonia. J . Infect. Dis. 1990, 161, 91-
96.
(36) Masur, H.; Polis, M. A.; Tuazon, C. V.; Ogota, A. D.; Kovacs, J .
A.; Katz, D.; Hilt, D.; Simmons, T.; Feuerstein, I.; Lundgren,
B.; Lane, H. C.; Chabner, B. A.; Allegra, C. J . Salvage Trial of
Trimetrexate-Leucovorin for the Treatment of Cerebral Toxo-
plasmosis. J . Infect. Dis. 1993, 167, 1422-1426.
(37) Falloon, J .; Allegra, C. J .; Kovacs, J .; O’Neill, D.; Ogata-Arakaki,
D.; Feuerstein, I.; Polis, M.; Davey, R.; Lane, H. C.; LaFon, S.;
Rogers, M.; Zunich, K.; Turlo, J .; Tuazon, C.; Parenti, D.; Simon,
G.; Masur, H. Piritrexim with Leucovorin for the Treatment of
Pneumocystis Pneumonia (PCP) in AIDS Patients. Clin. Res.
1990, 38, 361A.
(38) Chabner, B. A. In Pharmacologic Principles of Cancer Treatment;
Chabner, B. A., Ed.; W. B. Saunders: Philadelphia, 1982; pp
229-238.
(39) For a review, see the following. Bodor, N.; Buchwald, P. Soft
Drug Design: General Principles and Recent Applications. Med.
Res. Rev. 2000, 20, 58-101.
(40) Clissold, S. P.; Heel, R. C. Budesonide. A Preliminary Review
of Its Pharmacodynamic Properties and Therapeutic Efficacy in
Asthma and Rhinitis. Drugs 1984, 28, 485-518.
(41) J ohansson, S.-Å.; Andersson, K.-E.; Brattsand, R.; Gruvstad, E.;
Hedner, P. Topical and Systemic Glucocorticoid Potencies of
Budesonide and Beclomethasone Dipropionate in Man. Eur. J .
Clin. Pharmacol. 1982, 22, 523-529.
(42) Graffner-Nordberg, M.; Sjo¨din, K.; Tunek, A.; Hallberg, A.
Synthesis and Enzymatic Hydrolysis of Esters, Constituting
Simple Models of Soft Drugs. Chem. Pharm. Bull. (Tokyo) 1998,
46, 591-601.
(43) Lindgren, B. O.; Nilsson, T. Preparation of Carboxylic Acids from
Aldehydes (Including Hydroxylated Benzaldehydes) by Oxida-
tion with Chlorite. Acta Chem. Scand. 1973, 27, 888-890.
(44) Kraus, G. A.; Roth, B. Synthetic Studies toward Verrucarol. 2.
Synthesis of the AB Ring System. J . Org. Chem. 1980, 45, 4825-
4830.
(45) Kraus, G. A.; Taschner, M. J . Model Studies for the Synthesis
of Quassinoids. 1. Construction of the BCE Ring System. J . Org.
Chem. 1980, 45, 1175-1176.
(46) Taylor, E. C.; Otiv, S. R.; Durucasu, I. Protection and Depro-
tection of Fused 2-Amino-4(3H)-pyrimidinones. Conversion of
Pterins and 5-Deazapterins to 2,4-Diamino Derivatives. Hetero-
cycles 1993, 36, 1883-1895.
(47) Davoll, J .; J ohnson, A. M. Quinazoline Analogues of Folic Acid.
J . Chem. Soc. 1970, 997-1002.