engleski

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-didehydro-5, 6-dideoxy-L-ascorbic acid were synthesized by the condensation of pyrimidine bases 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-acetyl-6-bromo-2, 3-dibenzyl-L-ascorbic acis (ABDA), while the reaction of 6-(N-pyrroly)purine with ABDA afforded exclusively the N-9 isomer 9. Structures of all newly prepared compounds were deduced from the chemical shifts in 1H and 13C NMR spectra, as well as connectivities in 2D homo- and heteronuclear correlation spectra. An unambiguous proof of the structure and conformation 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), cercival carcinoma (HeLa), laryngeal carcinoma (Hep2), murine leukemia (L1210/0), murine mammary carcinoma (FM3A), and human T-lymphocytes (Molt4/C8 and CEM/0), as well as antiviral activities against varicella-zoster virus (TK+VZV and TK-VZV) and cytomegalovirus (CMV). The compound 6 containing a triofluoromethyl-substituted uracil ring exhibited marked antitumor activity. The N-7-substituted purine regioisomer 8 had greater inhibitory effects on the murine L1210/0 and human CEM/0 cell lines than the N-9 isomer 7. Compound 9 with the 6-purine-substituted pyrrolo moiety had a more pronounced selective cytostatic activity against human (Molt4/C8 and CEM/0) cell lines than murine (L1210/0 and FM3A/0) and human (MiaPaCa2, MCF7, HeLa, and hep2) tumor cell lines and normal fibroblasts (Hef522). The compound 6 exhibited the most potent antiviral activities against TK+VZV, TK-VZV, and CMV, albeit at concentrations that were only slightly lower than the cytotoxic concentrations.

pyrimidine and purine derivatives ; L-ascorbic acid ; Murine leukemia (L1210/0) ; Murine mammary carcinoma (FM3A) ; Human T-lymphocytes (Molt4/C8 and CEM/0) ; Varicella-zoster virus (VZV) ; Cytomegalovirus (CMV)

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