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11) (a) Rosowsky, A.; Forsch, R. A.; Queener, S. F. Inhibition of
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(21) Kovacs, J . A.; Allegra, C. J .; Beaver, J .; Boarman, D.; Lewis,
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(22) Rosowsky, A.; Cody, V.; Galitsky, N.; Fu, H.; Papoulis, A. T.;
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dihydrofolate reductase: synthesis and antiparasitic activity of
2,4-diaminopteridine analogues with a bridged diarylamine side
chain. J . Med. Chem. 1999, 42, 4853-4860.
(23) Cody, V.; Galitsky, N.; Luft, J . R.; Pangborn, W.; Rosowsky, A.;
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(24) Rosowsky, A.; Fu, H.; Queener, S. F. Synthesis of new 2,4-
diaminopyrido[2,3-d]pyrimidines and 2,4-diaminoquinazolines
with bulky dibenz[b,f]azepine and dibenzo[a,d]cycloheptene sub-
stituents at the 6-positiion as inhibitors of dihydrofolate reduc-
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systems. Part IX. Synthesis and substitutions of dibenzo[b,f]-
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(ω-carboxyalkyloxy)benzyl]pyrimidines: Marked improvement
in potency relative to trimethoprim and species selectivity
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Rosowsky, A.; Forsch, R. A.; Queener, S. F. Further studies on
2
,4-diamino-5′-(2′, 5′-disubstituted benzyl)pyrimidines as potent
and selective inhibitors of dihydrofolate reduces from three major
opportunistic pathogens of AIDS. J . Med Chem. 2003, 46, 1726-
1
1
736; see this paper for a list of papers from this laboratory from
993 to 2002.
(
(
(
12) (a) Gangjee, A.; Dubash, N. P.; Queener, S. F. The synthesis of
new diaminofuro[2,3-d]pyrimidines with 5-biphenyl, phenoxy-
phenyl and tricyclic substitutions as dihydrofolate reductase
inhibitors. J . Heterocycl. Chem. 2000, 37, 935-942; see also
many other papers from this group prior to 2000. (b) Gangjee,
A.; Adair, O.; Queener, S. F. Synthesis of 2,4-diamino-6-(thio-
arylmethyl)pyrido[2,3-d]pyrimidines as dihydrofolate reductase
inhibitors. Bioorg. Med. Chem. 2001, 9, 2929-2935. (c) Gangjee,
A.; Zheng, Y.; McGuire, J . J .; Kisliuk, R. L. Synthesis of classical
and nonclassical, partially restricted, linear, tricyclic 5-deazaan-
tifolates. J . Med. Chem. 2002, 45, 5173-5181.
13) (a) Piper, J . R.; J ohnson, C. A.; Krauth, C. A.; Carter, R. L.;
Hosmer, C. A.; Queener, S. F.; Borotz, S. E.; Pfefferkorn, E. R.
Lipophilic antifolates as agents against opportunistic infections.
1
. Agents superior to trimetrexate and piritrexim against
Toxoplasma gondii and Pneumocystis carinii in in vitro evalu-
ations. J . Med. Chem. 1996, 39, 1271-1280. (b) Suling, W. J .;
Seitz, L. E.; Pathak, V.; Westbrook, L.; Barrow, E. W.; Zywno-
van Ginkel, S.; Reynolds, R. C.; Piper, J . R.; Barrow, W. R.
Antimycobacterial activities of 2,4-diamino-5-deazapteridine
derivatives and effects on mycobacterial dihydrofolate reductase.
Antimicrob. Agents Chemother. 2000, 44, 2784-2793.
14) (a) Stevens, M. F. G.; Phillip, K. S.; Rathbone, D. L.; O’Shea, D.
M.; Queener, S. F.; Schwalbe, C. H.; Lambert P. A. Structural
studies on bioactive compounds. 28. Selective activity of triaz-
enyl-substituted pyrimethamine derivatives against Pneumocys-
tis carinii dihydrofolate reductase. J . Med. Chem. 1997, 40,
(27) (a) Stadler, P. A.; Frey, A. J .; Troxler, R.; Hofmann, A. Selective
reduction and oxidation reactions of lysergic acid derivates. Helv.
Chim. Acta 1964, 47, 756-769. (b) Saa, J . M.; Capo, M.; Marti,
C.; Garcia-Raso, A. Oxidative degradation of 6-hydroxy-1,2,3,4-
tetrahydroisoquinolines and 7-hydroxy-2-benazepines. A novel
route to heterocyclic quinones. J . Org. Chem. 1990, 55, 288-
292. (c) Islam, L.; Skibo, E. B.; Dorr, R. T.; Alberts, D. S.
Structure-activity studies of antitumor agents based on pyrrolo-
[1,2-a]benzimidazoles: New reductive alkylating DNA cleaving
agents. J . Med. Chem. 1991, 34, 2954-2961. (d) Giethlen, B.;
1
886-1893. (b) Cody, V.; Chan, D.; Galitsky, N.; Rak, D.; Luft,
J . R.; Pangborn, W.; Queener, S. F.; Laughton, C. A.; Stevens,
M. F. G. Structural studies on bioactive compounds. 30. Crystal
structure and molecular studies on the Pneumocystis carinii
dihydrofolate reductase cofactor complex with TAB, a highly
selective antifolate. Biochemistry 2000, 39, 3556-3564.
(
15) Robson, C.; Meek, M. A.; Grunwaldt, J .-D.; Lambert, P. A.;
Queener, S. F.; Schmidt, D.; Griffin, R. J . Nonclassical 2-di-
amino-5-aryl-6-ethylpyrimidine antifolates: Activity as inhibi-
tors of dihydrofolate reductase from Pneumocystis carinii and
Toxoplasma gondii and as antitumor agents. J . Med. Chem.
Schaus, J . M. Oxidation of indolines with Fremy’s salt:
A
mechanistic proposal. Tetrahedron Lett. 1997, 38, 3483-3486.
(d) Kraus, G. A.; Selvakumar, N. A novel Fremy’s salt-mediated
oxidation and rearrangement of anilines into amino ortho-
diketones. Applications to the synthesis of pyrrolobenzodiaz-
epines. Tetrahedron Lett. 1999, 40, 2039-2040.
1
997, 40, 3040-3048.
(
16) For selected clinical examples, see: (a) Fischl, M. A.; Dickinson,
G. M.; La Voie, L. Safety and efficacy of sulfamethoxazole and
trimethoprim prophylaxis for Pneumocystis carinii pneumonia
in AIDS. J . Am. Med. Assoc. 1988, 259, 1185-1189. (b) Medina,
I.; Mills, H, Leuong, G.; Hopewell, P. C.; Lee, B.; Modin, G.;
Benowitz, N.; Wofsy, C. B. Oral therapy for Pneumocystis carinii
pneumonia in the acquired immunodeficiency syndrome. A
controlled trial of trimethoprim-sulfamethoxazole versus tri-
methoprim-dapsone. N. Engl. J . Med. 1990, 323, 776-782. (c)
Podzamczer, D.; Salazar, A.; J imenez, J .; Consiglio, E.; Santin,
M.; Casanova, A.; Rufi, G.; Gudiol, G. 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. (d) Fraser, I.; Macintosh, I.; Wilkins,
E. G. Prophylactic effect of co-trimoxazole for Mycobacterium
avium complex infection: a previously unreported benefit. Clin.
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(28) Taylor, E. C.; Portnoy, R. C.; Hochstetler, D. C.; Kobayashi, T.
Pteridines. XXXVIII. Synthesis of some 2,4-diamino-6-substi-
tuted methylpteridines. A new route to pteroic acid. J . Org.
Chem. 1975, 40, 2347-2351.
(29) Rosowsky, A.; Forsch, R. A.; Queener, S. F.; Bertino, J . R.
Synthesis of 2,4-diaminopteridines with bulky lipophilic groups
at the 6-position as inhibitors of Pneumocystis carinii, Toxo-
plasma gondii, and mammalian dihydrofolate reductase. Pte-
ridines 1997, 8, 173-187.
(30) Kuyper, L. F.; Roth, B.; Baccanari, D. P.; Ferone, R.; Beddell,
C. R.; Champness, J . N.; Stammers, D. K.; Dann, J . G.;
Norrington, F. E.; Baker, D. J .; Goodford. P. J . Receptor-based
design of dihydrofolate reductase inhibitors: comparison of
crystallographically determined enzyme binding with enzyme
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logues. J . Med. Chem. 1985, 28, 303-311.
(31) Broughton, M. C.; Queener, S. F. Pneumocystis carinii dihydro-
folate reductase used to screen potential antipneumocystis drugs.
Antimicrob. Agents Chemother. 1991, 35, 1348-1355.
(
17) 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,
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selective inhibitors of Toxoplasma gondii dihydrofolate reduc-
tase. Antimicrob. Agents Chemother. 1993, 37, 1914-1923. Note
that in our original paper in which the activity of 6 against T.
1
383-1386.
(
18) Ma, L.; Borio, L.; Masur, H.; Kovacs, J . A. Pneumocystis carinii
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or dapsone use. J . Infect. Dis. 1999, 180, 1969-1978.
2
2
3
gondii tachyzoites was reported the reference cited for the [ H]-
uracil incorporation assay method should have been 16b instead
of 17c.
(
19) (a) Sattler, F. R.; Frame, P.; Davis, R.; Nichols, L.; Shelton, B.;
Akil, B.; Baughman, R.; Hughlett, C.; Weiss, W.; Boylen, C. T.;
van der Horst, C.; Black, J .; Powderly, W.; Steigbigel, R. T.;
Leedom, J . M.; Masur, H.; Feinberg, J .; Benoit, S.; Eyster, E.;
Gocke, D.; Beck. K.; Lederman, M.; Phari, J .; Reichman, R.;
Sacks, H. S.; Soiero, R.. Trimetrexate with leucovorin versus
trimethoprim-sulfamethoxazole for moderate to severe episodes
of Pneumocystis carinii pneumonia in patients with AIDS: a
prospective, controlled multicenter investigation of the AIDS
Clinical Trials Group Protocol 029/031. J Infect. Dis. 1994, 170,
(33) Then, R. L.; Hartman, P. G.; Kompis, I.; Stephan-G u¨ ldner, M.;
St o¨ ckel, K. Epiroprim. Drugs Future 1994, 19, 446-449.
(34) 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.
(35) Wang, Y.; Bruenn, J . A.; Queener, S. F.; Cody, V. Isolation of
rat dihydrofolate reductase gene and characterization of recom-
binant enzyme. Antimicrob. Agents Chemother. 2001 45, 2517-