Synthesis, transformations and biological activity of sugar modified 5-substituted 2'-deoxyuridines
S. Ya. Melnik, A. A. Bakhmedova, I. V. Yartseva, O. S. Zhukova, N. P. Yavorskaya
All-Union Cancer Research Center, Academy of Medical Sciences of the USSR, Moscow
Abstract: 5-Benzyloxymethyl(Bom)-2'-deoxyuridine and its α-anomer were used as the key compounds for syntheses of thymidine analogues or 3'-derivatives. Anomeric 5-Bom-2'-deoxyuridines were synthesized from 5-Bom-uracil and 2-deoxy-3,5-di-O-p-toluyl-α-D-ribo-furanosyl chloride by means of the silyl method. 5-Bom-2'-deoxyuridine was transformed successively to 3',5'-di-O-mesyl derivative, 2,3'-anhydro-1-(2-deoxy-5-O-p-toluyl-β-D-xylofuranosyl)-5-Bom-uracil and 3'-azido-2',3'-dideoxy-5-Bom-uridine. Treatment of the last with SnCl4 in methylene dichloride – methanol led to 3'-azido-2',3'-dideoxy-5-methoxymethyluridine. Under the same conditions the 5-methoxymethyl derivative was obtained from 3',5'-di-O-p-toluyl-5-Bom-2'-deoxyuridine. Interaction of l-(2-deoxy-α-D-ribofuranosyl)-4-Bom-uracil with SnCl4 in methylene dichloride as well as the hydrogen transfer hydrogenolysis in the presence of cyclohexene and Pd(OH)2/C in ethanol led to 1-(2-deoxy-α-D-ribofuranosyl)-5-hydroxymethyluracil. Only 3'-azido-2',3'-dideoxy-5-Bom-uridine showed a cytotoxic activity against CaOv cells in vitro: in 10-5–10-4 M concentrations it inhibits the thymidine incorporation into DNA by 78,8–95,1%. Elucidation of antitumour activity in vivo showed that this nucleoside inhibits growth of solid tumours, Ca755 and LLC, by 79 and 79–83%, respectively, but has no therapeutic effect against lympholeukemia P388.
Russian Journal of Bioorganic Chemistry 1991, 17 (8):1101-1110