In view of the marked antitumor activity of 3-deazauridine, the synthesis of 4-(beta-D-ribofuranosyl)-1,3-dihydroxybenzene (1,3-dideazauridine) and its dibenzyl derivative was carried out. 4-Bromo-1,3-dihydroxybenzene was converted to its dibenzyl derivative, which, upon reaction with n-butyllithium followed by treatment with anhydrous cadmium chloride, gave bis(1,3-dibenzyloxyphenyl-4)cadmium. Condensation of this intermediate with 2,3,5-tri-O-benzoyl-D-ribofuranosyl chloride in refluxing toluene, and subsequent removal of the protecting benzoyl groups, afforded 4-(beta-D-ribofuranosyl)-1,3-dibenzyloxybenzene which, upon catalytic hydrogenation over Pd/C, furnished the desired 4-(beta-D-ribofuranosyl)-1,3-dihydroxybenzene. The beta configuration at the anomeric center was established by NMR and hydrogen bonding studies. 4-(Beta-D-ribofuranosyl)-1,3-dibenzyloxybenzene inhibited the growth of leukemia L1210 cells by 50% at 7 x 10(-6) M, and that of mammary carcinoma TA3 cells at 5 x 10(-5) M. Dideazauridine itself was less active, inhibiting the leukemia L1210 but not the TA3 cells at 1 x 10(-4) M, but the compound was significantly active against herpes simplex (type I) virus in vitro.

3-Deazauridine↗

PubMed1975

Inhibitors of protein synthesis. 4. Studies on the structure-activity relationship of gougerotin and some of its analogs.

Seventeen structural analogs of gougerotin have been compared with the parent compound as inhibitors of the growh of E. coli B and as inhibitors of N-acetylphenylalanylpuromycin formation. The analogs comprise compounds with (1) an intact sarcosyl-D-seryl moiety and modifications at various positions of the carbohydrate moiety, (2) compounds which lack the peptidyl residue, and (3) compounds in which the sarcosyl-D-seryl moiety has been replaced by other aminoacyl or peptidyl moieties and in which various sites in the carbohydrate moiety have been modified in addition. These comparisons revealed that (1) the 3'-hydroxyl group makes a strong contribution to inhibitory activity, (2) the introduction of a double bond between the 2' and 3' positions of the carbohydrate moiety causes a marked decrease in activity; however, if in addition the sarcosyl-D-seryl moiety is replaced by the epsilon-N-methyl-beta-L-arginyl side chain, full activity is restored, (3) there is a marked degree of stereospecificity around the alpha carbon of the seryl moiety (replacement of the sarcosyl-D-seryl residue with the sarcosyl-L-seryl residue results in greatly reduced activity), and (4) replacement of the carboxamide group at position 5' with a hydroxymethyl function resulsts in reduced activity which is further decreased by alterations in the sarcosyl-D-seryl moiety. These alterations include (a) replacement of the D-seryl residue of the sarcosyl-D-seryl moiety by the D-alanyl or the D-phenylalanyl residues and (b) replacement of the whole sarcosyl-D-seryl side chain by the D-seryl, D-alanyl, D-phenylalanyl, p-methoxy-D-phenylalanyl, or p-methoxy-L-phenylalanyl moieties; the replacement of the sarcosyl-D-seryl side chain with the various aminoacyl residues did not lead to acceptor (puromycin-like) activity with N-Ac-Phe-tRNA as the donor.

Aminoglycosides↗

PubMed1975

Synthesis and biological activity of 5-fluoro-4'-thiouridine and some related nucleosides.

The synthesis of a series of 4'-thio-5-halogenopyrimidine nucleosides, including the 5-fluoro, chloro, bromo and iodo derivatives, has been carried out by condensation of the 2,4-bis-O-trimethylsilyl derivatives of the corresponding pyrimidine bases with the protected 4-thio-D-ribofuranosyl chloride. Among these, the alpha and beta anomers of 4'-thio-5-fluorouridine inhibited the growth of leukemia L1210 cells at concentrations of 4 x 10(-7) and 2 x 10(-7) M, respectively, and that of S. faecium at 4 x 10(-9) and 6 x 10(-10) M, respectively. These compounds retained marked activity against strains of S. faecium resistant to 10(-3) M 5-fluorouracil or 5-fluorouridine. As determined in S. faecium cultures, 4'-thio-5-fluorouridine decreased the total protein content of the cells more markedly than it did their RNA or DNA content. X-Ray crystallography showed that substitution of sulfur for the oxygen in the carbohydrate ring markedly changes the conformation of that moiety.

Animals↗

PubMed1975

Preparation and biological activity of some aminoacyl and peptidyl derivatives of 2'-amino-2'-deoxyuridine.

Several aminoacyl and peptidyl derivatives of 2'-amino-2'-deoxyuridine have been synthesized. 2'-Amino-2'-deoxyuridine (I) and 2'-N-glycyl-2'-amino-2'-deoxyuridine (IIIa) were condensed with N-Cbz blocked p-nitrophenyl esters of the appropriate amino acids to afford the protected aminoacyl and peptidyl nucleosides. Removal of the protecting groups gave the title compounds in good yields. The biological effects of these derivatives are discussed.

Deoxyuridine↗

PubMed1975