Synthesis and antitumor activities of novel pyrimidine derivatives of 2,3-O,O-dibenzyl-6-deoxy-L-ascorbic acid and 4,5-didehydro-5,6-dideoxy-L-ascorbic acid

The new pyrimidine derivatives of 2,3-O,O-dibenzyl-6-deoxy-L-ascorbic acid (8-10) were synthesized by condensation of uracil and its 5-fluoro- and 5-t rifluoromethyl-substituted derivatives with 4-(5,6-epoxypropyl)-2,3-O,O-dib enzyl-L-ascorbic acid (7), while pyrimidine derivatives of 4,5-didehydro-5, 6-dideoxy-L-ascorbic acid (14-17) with free C-2' and C-3' hydroxy groups in the lactone ring were obtained by debenzylation of 11-13 with boron trichl oride. Z-Configuration of the C4'=C5' double bond and position of the benzy l group in the lactone ring of 14 were deduced from their H-1 and C-13 NMR spectra and connectivities in COSY, ROESY, and HMBC spectra. The exact ster eostructure of 13 was confirmed by its X-ray crystal structure analysis. Of all the compounds in the series, compound 16 containing a 5-fluoro-substit uted uracil ring showed the most significant antitumor activities against m urine leukemia L1210/0 (IC50 = 1.4 mug/mL), murine mammary carcinoma FM3A/0 (IC50 = 0.78 mug/mL), and, to a lesser extent, human T-lymphocyte cells Mo lt4/C8 (IC50 = 31.8 mug/mL) and CEM/0 cell lines (IC50 = 20.9 mug/mL).