Synthesis and biological evaluation of unsaturated keto and exomethylene d-arabinopyranonucleoside analogs: Novel 5-fluorouracil analogs that target thymidylate synthase

• Published in: European journal of medicinal chemistry 2011-04, Vol.46 (4), p.993-1005
• Main Authors: Tzioumaki, Niki, Manta, Stella, Tsoukala, Evangelia, Voorde, Johan Vande, Liekens, Sandra, Komiotis, Dimitri, Balzarini, Jan
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil prodrugs; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiviral; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fluorouracil - analogs & derivatives; Fluorouracil - chemical synthesis; Fluorouracil - pharmacology; General aspects; Humans; Inhibitory Concentration 50; Ketonucleosides; Medical sciences; Mice; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Pharmacology. Drug treatments; Substrate Specificity; Thymidylate Synthase - antagonists & inhibitors; Thymidylate Synthase - metabolism; Unsaturated nucleosides; Uridine Phosphorylase - antagonists & inhibitors; Uridine Phosphorylase - metabolism; Viruses - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.01.005

The synthesis of pyrimidine unsaturated keto and exomethylene arabinopyranonucleoside analogs as potential antitumor and antiviral agents is described. Commercially available 1,2,3,4-tetra- O-acetyl- d-arabinopyranose ( 1) was condensed with silylated thymine, uracil, 5-fluorouracil, N 4-benzoyl cytosine and 5-(trifluoromethyl)uracil, respectively, deacetylated and acetylated to afford 1-(3,4- O-isopropylidene- α- d-arabinopyranosyl)pyrimidine analogs 4. Two different synthetic routes were investigated for the conversion of compounds 4 into the new 1-(2,3,4-trideoxy-2-methylene- α-pent-3-enopyranosyl)nucleoside derivatives of thymine ( 10a), uracil ( 10b), 5-fluorouracil ( 10c) and N 4-benzoyl cytosine ( 10d). Only the first approach could afford derivative 10d. Debenzoylation of 10d afforded 1-(2,3,4-trideoxy-2-methylene- α-pent-3-enopyranosyl)cytosine ( 10f). The first approach resulted also to the 2-keto-3,4-unsaturated analogs 9. The new analogs did not show inhibition of DNA and RNA virus replication in cell culture. The 2′-ketonucleoside derivatives 9 were found to be more cytostatic than the corresponding 2′-exomethylene nucleosides 10. The 5-fluorouracil unsaturated keto derivative 9c and the exomethylene derivatives 10c and 13c showed antiproliferative activity in the lower micromolar range. Experimental evidence revealed that 9c, 10c and 13c may act as novel types of 5-fluorouracil releasing prodrugs, and points to thymidylate synthase as target for their cytostatic action. Ketonucleosides were found to be more cytostatic than the corresponding exomethylene nucleosides. The 5-fluorouracil exomethylene derivatives 10c and 13c and the unsaturated keto derivative 9c showed antiproliferative activity in the lower micromolar range. Experimental evidence revealed that 9c, 10c and 13c may act as novel types of 5-fluorouracil releasing prodrugs, and points to thymidylate synthase as target for their cytostatic action. [Display omitted] ► Synthesis of alfa/beta-unsaturated keto pyranonucleosides. ► Synthesis of alfa/beta-unsaturated exomethylene pyranonucleosides. ► Pronounced cytostatic activity when the base part represents 5-fluorouracil. ► Discovery of the novel type of 5-flurouracil releasing prodrug.