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)

Citation
Ji. Borrell et al., 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), J MED CHEM, 44(14), 2001, pp. 2366-2369
Citations number
23
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
44
Issue
14
Year of publication
2001
Pages
2366 - 2369
Database
ISI
SICI code
0022-2623(20010705)44:14<2366:SABO7S>2.0.ZU;2-W
Abstract
We recently described the syntheses of 12a-c, 4-amino-7-oxo substituted ana logues 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 avail able p-substituted methyl benzoates in: 20-27% overall yields; Such analogu es were tested in vitro against CCRF-CEM leukemia cells and showed that the y are completely devoid of any activity, the IC50 being higher than 20 mug/ mL for all cases. To clarify if the presence of the carbonyl group in posit ion C7, the distinctive feature of our synthetic. methodology, is the reaso n for this lack of activity, we have now obtained the 7-oxo substituted ana logues of 5-DATHF and DDATHF, 18a-c, in 10-30% overall yield. Testing of 18 a-c in vitro against CCRF-CEM leukemia cells revealed that these compounds are totally inactive. A molecular modeling study of 18b inside the active s ite of the complex El coli GARTFase-5-DATHF-GAR pointed to an electronic re pulsion between the atoms of the 7-ore group and the carbonyl group of Arg9 0 as a possible explanation for the inactivity of 18a-c.