Synthesis and antiviral and cytostatic evaluations of the new C-5 substituted pyrimidine and furo[2,3-d] pyrimidine 4′,5′-didehydro-L-ascorbic acid derivatives

The novel C-5 alkynyl substituted pyrimidine (1-11) and furo[2,3-d] pyrimidine derivatives (12-22) of L-ascorbic acid were synthesized by coupling of 5-iodouracil-4',5'- didehydro-5',6'-dideoxy-L-ascorbic acid with terminal alkynes by using Sonogashira cross-coupling reaction conditions. The new compounds were evaluated for their cytostatic and antiviral activities. Among all evaluated compounds, the octynyl-substituted uracil derivative of L-ascorbic acid (3) exhibited the most pronounced cytostatic activities against all examined tumor cell lines (IC50 = 2-12 mu M). Pyrimidine derivatives of L-ascorbic acid containing p-substituted phenylacetylene groups (8-11) displayed also a rather pronounced (IC50 = 3- 37 mu M) inhibitory effect toward all tumor cell lines. From the bicyclic series of compounds, 6-butylfuro[ 2,3-d] pyrimidine derivative (12) and 6-p-bromophenylfuro[2,3-d] pyrimidine derivative (19) showed the highest cytostatic activity (IC50) 4.5- 20 mu M), particularly against malignant leukemia (L1210) and T-lymphocyte (Molt4/C8 and CEM) cells. Compounds 3 and 9 showed specific albeit moderate activity against cytomegalovirus (CMV, Davis strain, EC50 = 1.8 and 3.8 AM, respectively, for compounds 3 and 9) at a similar to 5-fold lower concentration than that required to show cytotoxicity.