Studies on the syntheses of heterocyclic compounds. 845. Studies on the synthesis of chemotherapeutics. 10. Synthesis and antitumor activity of N-acyl- and N-(alkoxycarbonyl)-5-fluorouracil derivatives

Abstract

A number of N-acyl and N-(alkoxycarbonyl)-5-fluorouracil derivatives possessing, for example, benzoyl, o-toluyl, acetyl, propionyl, heptanoyl, ethoxycarbonyl, phenoxycarbonyl, and benzyloxycarbonyl groups as N1 and/or N3 substituents were synthesized, and their antitumor activities were evaluated. The synthesis was achieved by a direct and two-step acylation of 5-fluorouracil and by selective N1-deacetylation of N1-acetyl-N3-substituted-5-fluorouracil under appropriate reaction conditions. Several N3-benzoyl- and N3-o-toluyl-5-fluorouracil derivates and showed significant activity against experimental tumor, and N1-acetyl-N3-o-toluyl-5-fluorouracil was found to be most promising among them. Further investigation revealed 12 to retain higher activity toward various tumors, with lower toxicity and good blood level, than either 1 or FT-207, even for oral administration.

Discovery of a New Class of Highly Potent Inhibitors of Acid Ceramidase: Synthesis and Structure–Activity Relationship (SAR)

“…The tert -butyloxycarbonyl group was then removed with potassium carbonate in methanol to afford 3-alkyluracils 12a , b , 13a – 14a which were then converted into the corresponding carboxamides 8a , b , 9a – 10a following method A. Syntheses of N3-substituted uracils 15a – 19a were accomplished with minor modifications of literature procedures, as reported in Scheme , by direct N3-acylation of N 1-carboxamide derivatives. No decomposition of the ureidic function occurred in agreement with what observed with N 1-alkoxycarbonyluracils . Compound 15a was prepared starting from carmofur ( 4a ) by reaction with isobutyryl chloride in the presence of triethylamine.…”

“…The PDA range was 210−400 nm. Purifications were performed on a XBridge Prep C 18 OBD column (100 mm × 19 mm i. Hydrogenation reactions were performed using H-Cube continuous hydrogenation equipment (SS-reaction line version), employing disposable catalyst cartridges (CatCart) preloaded with the required heterogeneous catalyst. Microwave heating was performed using Explorer-48 positions instrument (CEM).…”

“…No decomposition of the ureidic function occurred in agreement with what observed with N1-alkoxycarbonyluracils. 18 Compound 15a was prepared starting from carmofur (4a) by reaction with isobutyryl chloride in the presence of triethylamine. The carbamoyl derivatives 16a−17a were obtained by treatment of 4a with the appropriate chloroformate in the presence of pyridine as base.…”

Ferrocenoyl‐Substituted Pyrimidine Nucleobases: An Experimental and Computational Study of Regioselective Acylation of Uracil, Thymine, and 5‐Fluorouracil

“…[13] It has been found that the N-acylation position depends on the reaction temperature, base, catalyst, and acylation agent employed. [14,15] In case of the reaction between thymine and FcCOCl, only one product was observed spectroscopically (Figure 2). The reaction was followed by the sampling method in which aliquots (0.2 mL) were taken directly from the reaction mixture at selected time points.…”

Ring-Expanded Nucleoside Analogues. 1,3-Dioxan-5-yl Pyrimidines

“…Preparation of cis- 5a − c was accomplished in satisfactory overall yield (29−59%) as shown in Scheme . Mitsunobu condensation of bis-1,3-trityloxy-2-propanol ( 6 ) with 3-benzoyluracil, 3-benzoyl-5-fluorouracil, and 3-benzoylthymine 18 ( 7a − c ) gave products 8a − c , respectively. Debenzoylation (ammonia in methanol, room temperature) followed by detritylation (80% acetic acid, 75 °C) afforded the necessary 1-(1,3-dihydroxy-2-propyl)pyrimidines 9a − c .…”