The goal of the proposed research is the identification of new agents that exert greater effectiveness in the antifolate therapy of human cancer than agents now available, particularly in regard to achieving a broader spectrum of antitumor response. The proposed work is concerned with design and synthesis of potential antifolates which will be subjected to biochemical-pharmacologic evaluation. Proposed potential antifolates are designed with the aim of exploiting differences in two biochemical parameters of antifolate action in tumors and normal proliferative tissue. These differences, which appear to be determining factors for selective antitumor activity, are in cellular membrane transport and in intracellular polyglutamylation. Earlier biochemical studies which identified the 5 and 10 positions of the classical antifolate molecular structure as sites where modifications affect transport and polyglutamylation have already led to therapeutically improved antifolates of the 10-deazaaminopterin series. Studies aimed toward possible similar exploitation in the 5-deaza series of antifolates are in progress under the program whose continuation we are requesting. Recent findings that enhance our understanding of the multiple effects of classical antifolates and their intracellular polyglutamate metabolites point to the need to include compounds designed to inhibit folate-dependent sites other than dihydrofolate reductase in our quest for antifolate agents of greater effectiveness. Accordingly, in addition to compounds proposed as potential improvements over the 10-deazaaminopterin type, we also propose to prepare several attractive analogs of 10- propargyl-5,8-dideazafolic acid (CB3717) and 5,10-dideaza-5,6,7,8- tetrahydrofolic acid (DDATHF). Compound CB3717, a thymidylate synthase inhibitor, is in clinical trial; DDATHF, believed to owe its activity mainly to inhibition of glycineamide ribonucleotide transferase, has been shown to be an effective in vivo antitumor agent. Compounds synthesized in the laboratory of the applicant will be supplied to the Laboratory for Molecular Therapeutics at Sloan-Kettering Memorial Cancer Center for biological and pharmacological evaluation. Two collaborators will also receive selected samples for specialized evaluation in a coordinated program for drug evaluation in accord with the potential capability of these compounds to exert a broader spectrum of antitumor effects than methotrexate. Evaluations will include ability to inhibit tumor cell growth in vitro, dihydrofolate reductase, thymidylate synthase, AICAR transformylase, GAR transformylase, and folylpolyglutamate synthetase. Transport characteristics in tumor and gut epithelial cells will also be studied. Selected compounds will be provided for study of in vivo activity in animal tumor systems.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA025236-10A1
Application #
3166758
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1979-04-01
Project End
1992-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
10
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Southern Research Institute
Department
Type
DUNS #
006900526
City
Birmingham
State
AL
Country
United States
Zip Code
35205
Reynolds, R C; Johnson, C A; Piper, J R et al. (2001) Synthesis and antifolate evaluation of the aminopterin analogue with a bicyclo. Eur J Med Chem 36:237-42
Piper, J R; Ramamurthy, B; Johnson, C A et al. (1996) Analogues of 10-deazaaminopterin and 5-alkyl-5,10-dideazaaminopterin with the 4-substituted 1-naphthoyl group in the place of 4-substituted benzoyl. J Med Chem 39:614-8
McGuire, J J; Heitzman, K J; Haile, W H et al. (1993) Cross-resistance studies of folylpolyglutamate synthetase-deficient, methotrexate-resistant CCRF-CEM human leukemia sublines. Leukemia 7:1996-2003
Piper, J R; Johnson, C A; Maddry, J A et al. (1993) Studies on analogues of classical antifolates bearing the naphthoyl group in place of benzoyl in the side chain. J Med Chem 36:4161-71
Piper, J R; Johnson, C A; Maddry, J A et al. (1993) Analogues of classical antifolates bearing naphthoyl in place of benzoyl. Adv Exp Med Biol 338:435-9
Piper, J R; Johnson, C A; Otter, G M et al. (1992) Synthesis and antifolate evaluation of 10-ethyl-5-methyl-5,10- dideazaaminopterin and an alternative synthesis of 10-ethyl-10- deazaaminopterin (edatrexate). J Med Chem 35:3002-6
Piper, J R; Malik, N D; Rhee, M S et al. (1992) Synthesis and antifolate evaluation of the 10-propargyl derivatives of 5-deazafolic acid, 5-deazaaminopterin, and 5-methyl-5-deazaaminopterin. J Med Chem 35:332-7
Blakley, R L; Piper, J R; Maharaj, G et al. (1991) Mobility of the spin-labeled side chains of some novel antifolate inhibitors in their complexes with dihydrofolate reductase. Eur J Biochem 196:271-80
Thorndike, J; Kisliuk, R L; Gaumont, Y et al. (1990) Tetrahydrohomofolate polyglutamates as inhibitors of thymidylate synthase and glycinamide ribonucleotide formyltransferase in Lactobacillus casei. Arch Biochem Biophys 277:334-41
Piper, J R; McCaleb, G S; Montgomery, J A et al. (1988) Synthesis and antifolate activity of 5-methyl-5,10-dideaza analogues of aminopterin and folic acid and an alternative synthesis of 5,10-dideazatetrahydrofolic acid, a potent inhibitor of glycinamide ribonucleotide formyltransferase. J Med Chem 31:2164-9

Showing the most recent 10 out of 14 publications