Abstract

The long term objective of this research is to aid in the development of new chemotherapeutic agents based on the properties of the folate enzyme dihydrofolate reductase and thymidylate synthase.
The specific aims for the three year grant period requested are: 1) Characterize the RNA fragments found as constituents of thymidylate synthase purified from methotrexate-resistant Streptococcus faecium. 2) Determine if the RNase sensitive macromolecular component to which thymidylate synthase is attached in crude extracts of methotrexate-resistant S. faecium can be found in methotrexate-sensitive organisms and in Lactobacillus casei strains sensitive and resistant to methotrexate. 3) Determine if other enzymes of deoxynucleotide synthesis such as ribonucleotide reductase and DNA polymerase are associated with the macromolecular component attached to thymidylate synthase in methotrexate-resistant S. faecium. 4) Determine the inhibitory activity of polyglutamate derivatives of 5,8-dideaza-10-propargyl folate for thymidylate synthase. 5) Determine the antimicrobial and enzyme inhibitory potency of diastereoisomers of 10-methyl-10-deazaminopterin. 6) To prepare S. faecium thymidylate synthase in a form suitable for X-ray studies. The methodologies to be employed include: microbiological assay, enzyme assay, affinity chromatography, high performance liquid chromatography, sucrose gradient sedimentation, and RNA sequencing. Through collaborative arrangements we have access to X-ray crystallography, large scale fermentations, organic synthesis and experimental chemotherapy in mouse tumor systems. Health relatedness- Thymidylate synthase is inhibited by a metabolite of the antitumor agent fluorouracil and dihydrofolate reductase is inhibited by methotrexate (antitumor agent) and trimethoprim (antibacterial agent). Our work leads to information which is useful in guiding the efforts of organic chemists to synthesize improved compounds.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA010914-18
Application #
3163389
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1978-01-01
Project End
1986-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
18
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111

  Publications

Hwang, Eung-Soo; Zhang, Zhigang; Cai, Haobin et al. (2009) Human cytomegalovirus IE1-72 protein interacts with p53 and inhibits p53-dependent transactivation by a mechanism different from that of IE2-86 protein. J Virol 83:12388-98
Gangjee, Aleem; Zeng, Yibin; Talreja, Tina et al. (2007) Design and synthesis of classical and nonclassical 6-arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as antifolates. J Med Chem 50:3046-53
Gangjee, Aleem; Yang, Jie; McGuire, John J et al. (2006) Synthesis and evaluation of a classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as antifolates. Bioorg Med Chem 14:8590-8
Gangjee, Aleem; Jain, Hiteshkumar D; Kisliuk, Roy L (2005) Novel 2-amino-4-oxo-5-arylthio-substituted-pyrrolo[2,3-d]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase. Bioorg Med Chem Lett 15:2225-30
Gangjee, Aleem; Lin, Xin; Kisliuk, Roy L et al. (2005) 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 dihydrofol J Med Chem 48:7215-22
Gangjee, Aleem; Zeng, Yibin; Ihnat, Michael et al. (2005) Novel 5-substituted, 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors with antiangiogenic and antitumor activity. Bioorg Med Chem 13:5475-91
Gangjee, Aleem; Jain, Hiteshkumar D; McGuire, John J et al. (2004) 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 47:6730-9
Gangjee, Aleem; Zeng, Yibin; McGuire, John J et al. (2004) Synthesis of classical, three-carbon-bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates. J Med Chem 47:6893-901
Gangjee, Aleem; Yu, Jianming; Kisliuk, Roy L et al. (2003) Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and J Med Chem 46:591-600
Kisliuk, R L (2003) Deaza analogs of folic acid as antitumor agents. Curr Pharm Des 9:2615-25

Showing the most recent 10 out of 36 publications