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Synthesis and Biological Activity of 7-Oxo Substituted Analogues of 5-Deaza-5,6,7,8-tetrahydrofolic Acid (5-DATHF) and 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid (DDATHF)

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posted on 2001-06-12, 00:00 authored by José I. Borrell, Jordi Teixidó, Josep Lluís Matallana, Blanca Martínez-Teipel, Carles Colominas, Marta Costa, Merche Balcells, Elisabeth Schuler, María José Castillo
We recently described the syntheses of 12ac, 4-amino-7-oxo substituted analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid (5-DATHF), and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF), in six steps from commercially available p-substituted methyl benzoates in 20−27% overall yields. Such analogues were tested in vitro against CCRF-CEM leukemia cells and showed that they are completely devoid of any activity, the IC50 being higher than 20 μg/mL for all cases. To clarify if the presence of the carbonyl group in position C7, the distinctive feature of our synthetic methodology, is the reason for this lack of activity, we have now obtained the 7-oxo substituted analogues of 5-DATHF and DDATHF, 18ac, in 10−30% overall yield. Testing of 18ac in vitro against CCRF-CEM leukemia cells revealed that these compounds are totally inactive. A molecular modeling study of 18b inside the active site of the complex E. coli GARTFase-5-DATHF-GAR pointed to an electronic repulsion between the atoms of the 7-oxo group and the carbonyl group of Arg90 as a possible explanation for the inactivity of 18ac.

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