Abstract

The overall goal of this project continues to be the design and synthesis of new antifolates for cancer chemotherapy, with particular emphasis on innovative approaches leading to dihydrofolate reductase (DHFR) inhibitors whose mode of action is designed to set them favorably apart from 'classical' inhibitors such as aminopterin (AMT), methotrexate (MTX), and edatrexate (EDX).
SPECIFIC AIM 1 : To extend and complete the currently ongoing work on tightly DHFR bound and efficiently transported but nonpolyglutamated analogs, of which the lead compound, N-alpha-(4-amino-4deoxypteroyl)- N-delta-hemiphthaloyl-L-ornithine (PT523, NSC 633713), was recently selected by the National Cancer Institute for accelerated preclinical development and Phase I testing as part of its new RAID program.
SPECIFIC AIM 2 : To synthesize a series of DHFR inhibitors which are good FPOS substrates but are limited to the addition of only one glutamyl residue. This will be accomplished by blocking free rotation of the side chain amide bond via the use of a bridge as has been done in the case of the potent thymidylate synthase inhibitor GW1843. These compounds will represent an intermediate class of DHFR inhibitors between those which are metabolized to longchain polyglutamates (e.g., MTX, EDX) and those which are not polyglutamated at all (e.g., PT523).
SPECIFIC AIM 3 : To synthesize a series of second generation analogs of 2-desamino-2-methylaminopterin (PT557, dmAMT), which was previously shown to be a weak DHFR inhibitor as the monoglutamate but a potent 'multitargeted antifolate' once it is metabolized intracellularly to polyglutamates. Because only the polyglutamates, and not the parent drug, will potently inhibit the target enzyme these compounds will more truly represent 'prodrugs' than AMT, and should therefore display improved selectivity against tumors with high FPGS activity relative to dose limiting host tissues. The focus will be on enhancing polyglutamation of the lead compound dmAMT by modification of the B-ring and/or pABA moiety.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA025394-23
Application #
6632963
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Lees, Robert G
Project Start
1990-04-01
Project End
2004-12-31
Budget Start
2003-05-01
Budget End
2004-12-31
Support Year
23
Fiscal Year
2003
Total Cost
$551,261
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Rosowsky, Andre; Forsch, Ronald A; Wright, Joel E (2004) Synthesis and in vitro antifolate activity of rotationally restricted aminopterin and methotrexate analogues. J Med Chem 47:6958-63
Wright, Joel E; Yurasek, Gregory K; Chen, Ying-Nan et al. (2003) Further studies on the interaction of nonpolyglutamatable aminopterin analogs with dihydrofolate reductase and the reduced folate carrier as determinants of in vitro antitumor activity. Biochem Pharmacol 65:1427-33
Vaidya, Chitra M; Wright, Joel E; Rosowsky, Andre (2002) Synthesis and in vitro antitumor activity of new deaza analogues of the nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523). J Med Chem 45:1690-6
Wright, Joel E; Rosowsky, Andre (2002) Synthesis and enzymatic activation of N-[N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithiny]-L-phenylalanine, a candidate for antibody-directed enzyme prodrug therapy (ADEPT). Bioorg Med Chem 10:493-500
Rosowsky, A; Wright, J E; Vaidya, C M et al. (2000) The effect of side-chain, para-aminobenzoyl region, and B-ring modifications on dihydrofolate reductase binding, influx via the reduced folate carrier, and cytotoxicity of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta Pharmacol Ther 85:191-205
Rosowsky, A; Wright, J E; Vaidya, C M et al. (2000) Analogues of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: synthesis and in vitro antitumor activity. J Med Chem 43:1620-34
Rosowsky, A (1999) PT523 and other aminopterin analogs with a hemiphthaloyl-L-ornithine side chain: exceptionally tight-binding inhibitors of dihydrofolate reductase which are transported by the reduced folate carrier but cannot form polyglutamates. Curr Med Chem 6:329-52
Wright, J E; Pardo, M; Tretyakov, A et al. (1998) Pharmacokinetics, antifolate activity and tissue distribution of PT523 in SCC VII tumor-bearing mice. Cancer Chemother Pharmacol 42:300-6
Rosowsky, A; Wright, J E; Vaidya, C M et al. (1998) Synthesis and potent antifolate activity and cytotoxicity of B-ring deaza analogues of the nonpolyglutamatable dihydrofolate reductase inhibitor Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl- L-ornithine (PT523). J Med Chem 41:5310-9
Johnson, J M; Meiering, E M; Wright, J E et al. (1997) NMR solution structure of the antitumor compound PT523 and NADPH in the ternary complex with human dihydrofolate reductase. Biochemistry 36:4399-411

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