This laboratory has been engaged for some time in the design, synthesis, and biological evaluation of derivatives and structural analogues of methotrexate (MTX), aminopterin (AMT), and other classical antifolates with the aim of producing new agents with improved pharmacological and therapeutic properties or a qualitatively altered spectrum of antitumor activity. The research is part of an ongoing collaborative effort with other groups sharing an interest in innovative approaches to antifolate drug development. An urgent goal of the work is to find compounds with an increased ability to accumulate in tumor cells which are MTX resistant because of a defect in their uptake mechanism for this drug. It is anticipated that cross-resistance between such compounds and MTX will be low, and that there will be the potential for clinical use against tumors with natural or acquired resistance to MTX. Since another important form of MTX resistance is known to involve structural alteration of the target enzyme dihydrofolate reductase (DHFR) resulting in decreased inhibition by MTX, a further goal of the work is to find compounds that will bind more tightly than MTX to this altered enzyme. Finally, since it increasingly recognized that inhibition of folate pathway enzymes other than DHFR offers a major approach to the selective killing of tumor cells, a third goal of the research is to generate compounds that will inhibit these other enzymes, in place of or in addition to DHFR.
Specific aims to be pursued include the synthesis and testing of the following compounds of the diaminopteridine type: (1) lipophilic MTX analogues with alkyl groups on the beta or gamma-carbon of glutamate; (2) chain-lengthened lipophilic analogues in which glutamate is replaced by S-carboxyalkyl-L-cysteine or S- carboxyalkyl-L-homocysteine; (3) """"""""stretched"""""""" MTX analogues than can inhibit both DHFR an thymidylate synthase; (4) AMT analogues containing a delta- or epsilon-modified ornithine side- chain as potential dual inhibitors of DHFR and folylpolyglutamate synthetase; and (5) MTX analogues in which the gamma-carboxyl is joined to an aminoboronic acid so as to give a product that forms a strong tetrahedral boronate complex to polar active-site residues in DHFR. In addition, we plan to synthesize and test a series of heretofore unstudied class of compounds consisting of 5,8,10-trideaza- and 6-aza-5,8,10-trideazatetrahydroaminopterin analogues and 5,8,10-trideaza- and 6-aza-5,8,10- trideazatetrahydrofolate analogues with H, Me, or Et substitution at position 10.
|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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