O-2',3'-Ketal-Nucleolipids of the Cytostatic 5-Fluorouridine: Synthesis, Lipophilicity, and Acidic Stability

The synthesis of a series of cyclic and acyclic O-2’,3’-ketal derivatives of the cancerostatic 5fluorouridine (2a) is described. The novel compounds were characterized by 1H- and 13C-NMR, and UV spectroscopy, as well as by elemental analyses. The lipophilicity values (log P, retention times in RP-18 HPLC) of the cyclic ketals were determined and related to the ring tensions as well as the acid stability of the spiro-linked ketal rings. 1. Introduction. – 5-Fluorouracil (1) as well as its b-d-ribo- and 2’-deoxy-b-dribonucleosides, 2a and 2b, respectively, possess antitumor activity against various types of carcinomas, particularly of the breast and the gastrointestinal tract. Furthermore, positive results have been obtained in the topical treatment of premalignant keratosis of the skin and basal cell carcinomas [1] [2]. The intrathecal use of 5-fluoro-2’deoxyuridine (2b) has been studied for meningeal dissemination of malignant brain tumors, and it has been found that this nucleoside has an excellent antitumor activity and minimal neurotoxicity [3]. A large number of lipophilic prodrugs of 5-fluorouracil (1) and its nucleosides have been prepared and found to possess useful antitumor properties. Besides Ftorafur and its derivatives [4 – 10], recently, 5-fluoro-5’-uridylic acid, mono[2-(decyloxy)-3-(dodecylsulfanyl)propyl]ester and its salts (Fosfluridine, Tidoxil) have been used for the treatment of intraepithelial proliferative diseases [11]. We now report the synthesis of lipophilic O-2’,3’-ketal nucleoside derivatives (nucleolipids) of compound 2a, and their lipophilicity as well as their stability towards acid. The motivation for this is our intention to embed such nucleolipids into hydrophobized nanotube arrays, for example, of TiO2 [12], and use them as implants for drug delivery.