Novel pyrimidine and purine derivatives of L-ascorbic acid: Synthesis and biological evaluation

The novel pyrimidine derivatives 1-6 of 2,3-dibenzyl-4,5-didehydro-5,6-dide oxy-L-ascorbic acid were synthesized by the condensation of pyrimidine base s with 5,6-diacetyl-2,3-dibenzyl-L-ascorbic acid (DDA). Both N-9 (7) and N- 7 (8) regioisomers were obtained in the reaction of 6-chloropurine with 5-a cetyl-6-bromo-2,3-dibenzyl-L-ascorbic acid (ABDA), while the reaction of 6- (N-pyrrolyl)purine with ABDA afforded exclusively the N-9 isomer 9. Structu res of all newly prepared compounds were deduced from the chemical shifts i n H-1 and C-13 NMR spectra, as well as connectivities in 2D homo- and heter onuclear correlation spectra. An unambiguous proof of the structure and con formation of 7 was obtained by X-ray crystallographic analysis. Compounds 1 -9 were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinom a (HeLa), laryngeal carcinoma (Hep2), murine leukemia (L1210/0), murine mam mary carcinoma (FM3A), and human T-lymphocytes (Molt4/C8 and CEM/0), as wel l as antiviral activities against varicella-zoster virus (TK(+)VZV and TK(- )VZV) and cytomegalovirus (CMV). The compound 6 containing a trifluoromethy l-substituted uracil ring exhibited marked antitumor activity. The N-7-subs tituted purine regioisomer 8 had greater inhibitory effects on the murine L 1210/0 and human CEM/0 cell lines than the N-9 isomer 7. Compound 9 with th e B-purine-substituted pyrrolo moiety had a more pronounced selective cytos tatic activity against human (Molt4/C8 and CEM-0) cell lines than murine (L 1210/0 and FM3A/O) and human (MiaPaCa2, MCF7, HeLa, and Hep2) tumor cell li nes and normal fibroblasts (Hef522). The compound 6 exhibited the most pote nt antiviral activities against TK(+)VZV, TK(-)VZV, and CMV, albeit at conc entrations that were only slightly lower than the cytotoxic concentrations.