.) The overall goal of the proposed work is the discovery of new agents against PC and TG infections, two life-threatening opportunistic diseases associated with AIDS and AIDS-related complex (ARC). More specifically, this project will focus on the design and synthesis of novel dicyclic and tricyclic diaminopyrimidine ring systems structurally related to the lipophilic dihydrofolate reductase (DHFR) inhibitors trimetrexate (TMX) and piritrexim (PTX). TMX and PTX have been found recently to have promising activity against PC and TG when given with folinic acid (FA) to protect host tissues from antifolate toxicity, and may offer some advantages over older antifolate drugs such as trimethoprim and the sulfonamides. Compounds to be synthesized in this project will include six general types of condensed diaminopyrimidine ring systems, and initial emphasis in each group will be on analogs with at least two methoxy groups in the aryl moiety, since this pattern already exists in TMX and PTX. However, the synthetic schemes will be general enough to allow preparation of congeners with other ring substituents, including, for example, halogens. Target compounds will be evaluated for their ability to inhibit DHFR mammalian cell and from PC and TG to determine whether selectivity is shown for either of the parasite enzymes. The compounds will also be tested for the ability to inhibit PC and TG proliferation in rat lung fibroblast monolayer culture in the presence of folinic acid. If any compound shows enough activity and selectivity in these in vitro assays, it will be re-synthesized on a larger scale to provide enough material for subsequent in vivo pharmacological and toxicological studies in mice or other animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029904-04
Application #
3144905
Study Section
Special Emphasis Panel (ARR (V3))
Project Start
1990-06-01
Project End
1995-05-31
Budget Start
1993-06-01
Budget End
1994-05-31
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Cody, Vivian; Pace, Jim; Chisum, Kim et al. (2006) New insights into DHFR interactions: analysis of Pneumocystis carinii and mouse DHFR complexes with NADPH and two highly potent 5-(omega-carboxy(alkyloxy) trimethoprim derivatives reveals conformational correlations with activity and novel parallel ring s Proteins 65:959-69
Chan, David C M; Fu, Hongning; Forsch, Ronald A et al. (2005) Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy-1-alkynyl substitution in the side chain. J Med Chem 48:4420-31
Chan, David C M; Rosowsky, Andre (2005) Synthesis of the lipophilic antifolate piritrexim via a palladium(0)-catalyzed cross-coupling reaction. J Org Chem 70:1364-8
Forsch, Ronald A; Queener, Sherry F; Rosowsky, Andre (2004) Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium. Bioorg Med Chem Lett 14:1811-5
Rosowsky, Andre; Forsch, Ronald A; Sibley, Carol Hopkins et al. (2004) New 2,4-diamino-5-(2',5'-substituted benzyl)pyrimidines as potential drugs against opportunistic infections of AIDS and other immune disorders. Synthesis and species-dependent antifolate activity. J Med Chem 47:1475-86
Rosowsky, Andre; Fu, Hongning; Chan, David C M et al. (2004) Synthesis of 2,4-diamino-6-[2'-O-(omega-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpteridines as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase. J Med Chem 47:2475-85
Rosowsky, Andre; Chen, Han; Fu, Hongning et al. (2003) 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 11:59-67
Rosowsky, Andre; Forsch, Ronald A; Queener, Sherry F (2003) Further studies on 2,4-diamino-5-(2',5'-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS. J Med Chem 46:1726-36
Cody, Vivian; Galitsky, Nikolai; Luft, Joseph R et al. (2002) Structure-based enzyme inhibitor design: modeling studies and crystal structure analysis of Pneumocystis carinii dihydrofolate reductase ternary complex with PT653 and NADPH. Acta Crystallogr D Biol Crystallogr 58:946-54
Rosowsky, Andre; Forsch, Ronald A; Queener, Sherry F (2002) Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines: marked improvement in potency relative to trimethoprim and species selectivity J Med Chem 45:233-41

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