The unsaturated acyclic nucleoside analogues bearing a sterically constrained ( Z)-4′-benzamido-2′-butenyl moiety: Synthesis, X-ray crystal structure study, cytostatic and antiviral activity evaluations

• Published in: Bioorganic & medicinal chemistry 2010-09, Vol.18 (17), p.6249-6257
• Main Authors: Benci, Krešimir, Wittine, Karlo, Radan, Malajka, Cetina, Mario, Sedić, Mirela, Kraljević Pavelić, Sandra, Pavelić, Krešimir, Clercq, Erik De, Mintas, Mladen
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - chemistry; Adenine - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiviral activity; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Cytostatic activity; Drug Screening Assays, Antitumor; Epoxy Compounds; General aspects; Humans; Isomerism; Medical sciences; Molecular Structure; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Supramolecular self-assembling; Unsaturated acyclic nucleoside analogues; X-ray diffraction
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.07.035

A series of the novel acyclic unsaturated pyrimidine ( 1– 12) and adenine ( 13) nucleoside analogues bearing conformationally restricted ( Z)-2′-butenyl moiety were synthesized and evaluated for their antiviral and cytostatic activity potency. The N-1 4″-fluoro-substituted-benzamide uracil derivative ( 7) showed inhibitory activity against the growth of MCF-7 cells at a concentration of 2.7 μM and no cytotoxic effect on normal fibroblasts WI38. The X-ray crystal structure analysis 11– 13 revealed supramolecular self-assemblies, in which infinite chains or dimers built two- and three–dimensional networks. A series of the novel acyclic unsaturated pyrimidine ( 1– 12) and adenine ( 13) nucleoside analogues bearing conformationally restricted ( Z)-2′-butenyl moiety were synthesized and evaluated for their antiviral and cytostatic activity potency against malignant tumor cell lines and normal human fibroblast (WI38). The N-1 and/or N-3 acyclic side chain substitution in pyrimidine ring in N-3 substituted 5-trifluoromethyluracil derivative ( 11), N-1, N-3 disubstituted 5-fluorouracil derivative ( 12) and adenine derivative ( 13) was deduced from their 1H and 13C NMR spectra and confirmed by single crystal X-ray structure analysis. The X-ray crystal structure analysis 11– 13 revealed also supramolecular self-assemblies, in which infinite chains or dimers built two- and three-dimensional networks. The results of the in vitro cytostatic activity evaluations of 1–13 indicate that the majority of the compounds tested exhibited a non-specific and moderate antiproliferative effect at the highest concentration (100 μM). Of all evaluated compounds on the cell lines tested only the N-1 4″-fluoro-substituted-benzamide uracil derivative ( 7) showed rather marked and selective inhibitory activity against the growth of MCF-7 cells at a concentration of 2.7 μM and no cytotoxic effect on normal fibroblasts WI38. This compound can be therefore considered as a potential antitumor lead compound for further synthetic structure modification.