| Autor: |
Moran, R G, Baldwin, S W, Taylor, E C, Shih, C |
| Zdroj: |
Journal of Biological Chemistry; December 1989, Vol. 264 Issue: 35 p21047-21051, 5p |
| Abstrakt: |
The diasteromers of 5,10-dideaza-5,6,7,8-tetrahydrofolate (DDATHF) differing in chirality about carbon 6 were resolved and studied as inhibitors of folate-dependent processes in mouse leukemia cells. Both diastereomers of DDATHF were found to be potent inhibitors of leukemia cell growth due to effects on de novopurine synthesis. Cell growth inhibition by these compounds was prevented by 5-formyltetrahydrofolate in a dose-dependent manner. This indicated that the effects of the DDATHF diastereomers were due to inhibition of folate-dependent processes. Metabolite reversal experiments indicated that 5‵-phosphoribosylglycinamide formyltransferase was the major site of action of these compounds in mouse cells. Another site in de novopurine synthesis was affected at higher concentrations of diastereomer B in L1210 cells. Low concentrations of both diastereomers were found to inhibit pure L1210 5‵-phosphoribosylglycinamide formyltransferase competitively with the folate substrate. The two diastereomers were also efficient substrates for mouse liver folylpolyglutamate synthetase. We conclude that the 6R- and 6S-diastereomers of DDATHF are remarkably similar and equiactive antimetabolites inhibitory to de novopurine synthesis and that the biochemical processes involved in their cytotoxicity display little stereochemical specificity. |
| Databáze: |
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