title: The novel C-5 aryl, alkenyl, and alkynyl substituted uracil derivatives of L-ascorbic acid: synthesis, cytostatic, and antiviral activity evaluations.
abstract: The novel C-5 substituted uracil derivatives of l-ascorbic acid were synthesized by coupling of 5-iodouracil-4,5-didehydro-5,6-dideoxy-l-ascorbic acid with unsaturated stannanes under Stille reaction conditions. The new compounds were evaluated for their antitumoral and antiviral activities. Among all compounds evaluated the 5-propynyl substituted uracil derivative of l-ascorbic acid (7) exhibited the most pronounced cytostatic activities against all examined tumor cell lines (IC(50): 0.2-0.78 microM). However, this compound was also cytotoxic to human normal fibroblasts WI 38. The 5-(phenylethynyl)uracil-2,3-di-O-benzylated l-ascorbic acid derivative (4) exhibited an albeit slight (IC(50): 55-108 microM), but selective inhibitory effect toward all tumor cell lines except for cervical carcinoma (HeLa), pancreatic carcinoma (MiaPaCa-2), laryngeal carcinoma (Hep-2), and colon carcinoma (SW 620), and no cytotoxicity to normal human fibroblast (WI 38). Compound 7 showed some, not highly specific, inhibitory potential against vesicular stomatitis virus, Coxsackie B4 virus, and Sindbis viruses (EC(50): 1.6 microM).
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Gazivoda
authors.forename: Silvana
authors.initials: S
authors.lastname: Raić-Malić
authors.forename: Marko
authors.initials: M
authors.lastname: Marjanović
authors.forename: Marijeta
authors.initials: M
authors.lastname: Kralj
authors.forename: Kresimir
authors.initials: K
authors.lastname: Pavelić
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Mladen
authors.initials: M
authors.lastname: Mintas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D011743:Pyrimidines / Q000737:chemistry; D013329:Structure-Activity Relationship; D014498:Uracil / Q000737:chemistry*; D014780:Viruses / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D007202:Indicators and Reagents; D011743:Pyrimidines; D014498:Uracil; D001205:Ascorbic Acid