Nucleosides and Nucleotides. 186. Synthesis and Biological Activities of Pyrimidine Carbocyclic Nucleosides with a Hydroxyamino Group Instead of a Hydroxymethyl Group at the 4'-Position of the Sugar Moiety

Abstract

Pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety were designed as potential antitumor and/or antiviral agents. Pd(O)-catalyzed reactions of enantiomerically pure (+)-(1R, 4S)-4-[(tert-butyldiphenylsilyl)oxy]-1-(ethoxycarbonyloxy)-2-cyclopentene (9) with N3-benzoylthymine and -uracil gave carbocyclic nucleosides 10 and 11. Subsequent Pd (O)-catalyzed reactions of N3-benzoyl-1-[(1R, 4S)-4-(ethoxycarbonyloxy)-2-cyclopenten-1-yl]thymne (14) and -uracil (15) with O-benzylhydroxylamine smoothly gave the hydroxyamino-substituted carbocyclic nuclesides 16 and 17. From these nucleosides, the target compounds were prepared after deprotection or further reactions. The 2', 3'-didehydro-2', 3'-dideoxythymidine (D4T) analogue 20 was the most effective compound, with IC₅₀ values of 27.3 and 34.5μM against KB and L1210 cells in vitor. Carbocyclic analogues of uridine and cytidine (29 and 32) were less effective than 20 against both cell lines.