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-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 acid (ABDA), while the reaction of 6-(N-pyrrolyl)purine with ABDA afforded exclusively the N-9 isomer 9. Structures of all newly prepared compounds were deduced from the chemical shifts in (1)H and (13)C 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), cervical 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 trifluoromethyl-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.
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulicev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia.
S
S
Raić-Malić
A
A
Hergold-Brundić
A
A
Nagl
M
M
Grdisa
K
K
Pavelić
E
E
De Clercq
M
M
Mintas
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D011687:Purines; D011743:Pyrimidines; D001205:Ascorbic Acid