Synthesis and antifolate properties of 9-alkyl-10-deazaminopterins.

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DeGraw JI, Christie PH, Kisliuk RL, Gaumont Y, Sirotnak FM

Synthesis and antifolate properties of 9-alkyl-10-deazaminopterins.

J Med Chem. 1990 Jan;33(1):212-5.

PubMed ID

2296020 [ View in PubMed

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Abstract

Reformatski condensation of benzyl 2-bromopropionate with 4-carbomethoxybenzaldehyde, followed by dehydration afforded benzyl 2-methyl-p-carbomethoxycinnamate (4a). Hydrogenation over a Pd catalyst gave the hydrocinnamic acid 5a. Conversion to the chloromethyl (6a) and azidomethyl ketone (7a) was followed by hydrogenation to the aminomethyl ketone (8a). Direct N-alkylation by 2,4-diamino-5-nitro-6-chloropyrimidine followed by reductive ring closure in Zn-HOAc and subsequent saponification of the benzoate ester yielded 4-amino-4-deoxy-9-methyl-10-deazapteroic acid (11a). Coupling with diethyl L-glutamate and saponification afforded 9-methyl-10-deazaminopterin (13a). The 9-ethyl analogue (13b) was similarly prepared from benzyl 2-bromobutyrate. The 9-methyl analogue (13a) was 21 times more potent than MTX as an inhibitor of cell growth in L1210 cells. The reason for this enhanced cytotoxicity in L1210 is unclear, since enzyme inhibition and transport parameters were similar to those of MTX. In human Manca leukemia cells growth inhibition was not dramatic and paralleled MTX.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Methotrexate	Dihydrofolate reductase	IC 50 (nM)	30	N/A	N/A	Details