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Abstract

Hether to unknown metabolically inert classical folate analog inhibitors of the enzyme Dihydrofolate Reductase ?DHFR! that are transported to tumor cells via the reduced folate receptors are provided. These compounds exhibit superior anti-asthmatic responses in rabbits relative to methotrexate and the standard drug theophylline. The title compound 4-amino-4-deoxy-5,8,10-trideaza-pteroyl-4'-methyleneglutamic acid (1) exhibited outstanding anti-tumor activity. Compound 1 was 1,000 to 10,000 times more active than methotrexate in causing total growth inhibition (TGI) of a number of human tumor cells in culture. Unlike methotrexate the the TGI values of 1 are in the range of therapeutically relevant concentrations. Tumor cells that are resistant to methotrexate by virtue of defective polyglutamylation were 3-4 times more collaterally sensitive to compound 1. 1 was completely inert on incubation with folylpolyglutamate synthetase. On treatment of 1 with a preparation of aldehyde oxidase no oxidative activity was uncovered. Compound 1 was totally resistant to hydrolytic cleavage of the glutamate moiety by carboxypeptidase derived from Pseudomonad sp. These biochemical and pharmacological properties of the metabolically inert classical antifolates establish their clinical utility and superiority as new and novel anti-inflammatory and anti-tumor agents exhibiting enhanced target enzyme specificity and lower toxicity.

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