Synthesis of cyclopentane analogs of 1-(2′,3′-dideoxy-β-glycero-pentofuranosyl)pyrimidine nucleosides

Abstract

Synthesis of new carbocyclic analogs of 1-(2′,3′-dideoxy-glycero-pentofuranosyl)pyrimidine nucleosides having the uracil (34), 2-thiouracil (33), 2-thiothymine (31), cytosine (44), and 5-methylcytosine (43) bases is described. The nucleoside analogs having the uracil, 2-thiouracil, and 2-thiothymine bases were prepared by coupling cis-3-aminocyclopentanemethanol (8) with 3-ethoxypropenoyl isocyanate (26), 3-ethoxypropenoyl isothiocyanate (25), and 3-methoxy-2-methylpropenoyl isothiocyanate (23), respectively, to give the corresponding acyl urea (30) and acyl thioureas (29 and 27). The acyl urea was cyclized in 2 N H2SO4 and the acyl thioureas in 15 N aqueous ammonia to give the corresponding nucleoside analogs. The nucleoside analogs containing the cytosine (44) and 5-methylcytosine (43) bases were prepared from the uracil and thymine nucleoside analogs, respectively, by way of the 4-chloropyrimidinone intermediates (42 and 41). The synthesis of cis-3-aminocyclopentanemethanol (8) from norbornene by way of cis-1,3-cyclopentanedicarboxylic acid anhydride (3) is also described. In addition, the ease of nucleophilic opening of compound 3 is compared to the opening of camphoric anhydride (9), which contains a cis-vicinal substituent at position 2. The relative ease of opening of compound 3 is discussed with respect to the effect, observed in an earlier study, that a cis-vicinal acetoxy group has on the course of the nucleophilic opening of such anhydrides. The 1H magnetic resonance spectra at 200 MHz of all of the synthetic intermediates and of the nucleoside analogs have been determined and discussed. The nucleoside analogs were screened for cell-growth inhibition using K-562 cells. Nucleoside analogs having the 2-thiouracil (33), 2-thiothymine (31), cytosine (44), and 5-methylcytosine (43) bases showed some growth inhibition with activity 150 to 300 times lower than that shown by 5-fluorouracil in this test system.