Biochemical Properties of 5-SULFUR-SUBSTITUTED Pyrimidine Nucleosides and Nucleotides (original) (raw)
Related papers
Journal of pharmaceutical sciences, 1966
Mercaptouracil (1) and 5-mercaptodeoxyuridine (11), structural analogs of thymine and thymidine, respectively, are effective growth inhibitors in various biological systems and under study as potential antineoplastic and antiviral agents. Both compounds were found to be extremely unstable in aqueous solutions as they undergo rapid autoxidation to the corresponding disulfides. Determination of the ultraviolet spectra and pKa values of the thiols was possible only by special techniques, using dithiothreitol (DTT) as a "protecting" agent. Both I and I1 have very low pKa's, and their anionic forms show characteristic absorption maxima in the 330-mp region. These results are discussed in comparison with the spectra and ionization equilibria of related compounds including some new S-substituted derivatives of I and 11. DTT was found to be also a uniquely suitable reagent for the preparation of pure I and I1 by stoichiornetric reduction of the corresponding disulhdes. A special technique was developed for the quantitative determination of the free thiols. STRUCTURAL analog of thymine ( I ) , 5-
The reactions of mercurated pyrimidine nucleotides with thiols and with hydrogen sulfide
Nucleic Acids Research, 1978
In the presence of thiols, 5-mercuripyrimidine nucleotides are quantitatively converted to 5-thiomercuri derivatives, but these compounds are unstable and decompose at a rate dependent on the nature of the thiol. The decomposition involves three different reactions and proceeds via a symmetrical mercury derivative of the nucleotide. The end product is the unmodified nucleotide. Similar reactions occur in the presence of hydrogen sulfide. Since mercurated nucleoside triphosphates are substrates for RNAand DNA polymerase only in the form of thiomercuri derivatives, this implies that when DNA is replicated or transcribed in vitro with a mercurated substrate, the latter is rapidly demercurated to the unmodified substrate which is incorporated as well. Hence the product of the in vitro synthesis can only be partially mercurated in any one pyrimidine. Also, formation of cross-links in the resulting polymer is possible.
5-Mercaptodeoxyuridine—Its enzymatic synthesis and mode of action in microbiological systems
Biochemical Pharmacology, 1969
5-Mercapto-2'-deoxyuridine (MUdR) was synthesized by enzymatic transfer of the deoxyribosyl group of thymidine (TdR) to 5-mercaptouracil (MU), by using the trans-N-dwxyribosylase from Lactobacillus helveticus. The acceptor and donor activities of MU, MUdR and their respective disulfides were studied in this enzyme system; the disulfides were found inactive as substrates, but they showed the same growth inhibitory activities as the corresponding thiols in the microbiological assays. MUdR was nearly as active as 5-fluoro-2'-dwxyuridine (FUdR) in the Lmtobacillus leichnmnii assay, but was considerably less active than FUdR in the Lactobacillus arabinosus and Streptococcus faecalis systems. Inhibition analysis studies indicated that MUdR, like FUdR, acts via inhibition of thymidylate synthetase. The significant differences found in the spectra of activities of MU and MUdR, as compared to those of 5-fluorouracil (FU) and FUdR, are related to differences in the routes and efficiency of their metabolic activation in which the mercapto analogs, due to the size of their 5-S-group, are restricted to the pathways available for the metabolic transformations of thymine and TdR, while the fluoro analogs may be converted to the nuclwtide via the uracil pathway. Some synergism and cross-resistance studies are also reported.
5-Substituted pyrimidine nucleosides and nucleotides
Chemical Society Reviews, 1977
Pyrimidine nucleosides and nucleotides bearing substituents other than hydrogen or methyl in the 5-position of the heterocyclic ring are analogues of natural components of nucleic acids and coenzymes. Many methods have been developed for their synthesis and the biological properties of these analogues have been widely studied. Polynucleotides containing 5-substituted pyrimidines have also been prepared and have been used to obtain information on the physical chemistry of polynucleotides.
Synthesis and biological activity of 5-fluoro-4'-thiouridine and some related nucleosides
Journal of Medicinal Chemistry, 1975
The synthesis of a series of 4'-thio-5-halogenopyrimidine nucleosides, including the S-flUOrO, chloro, bromo and iodo derivatives, has been carried out by condensation of the 2,4-bis-0-trimethylsilyl derivatives of the corresponding pyrimidine bases with the protected 4-thio-D-ribofuranosyl chloride. Among these, the CY and / 3 anomers of 4'-thio-5-fluorouridine inhibited the growth of leukemia L1210 cells at concentrations of 4 X and 2 X M , respectively, and that of S. faecium at 4 X lom9 and 6 X 10-lo M, respectively. These compounds retained marked activity against strains of S. faecium resistant to 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. Because of the pronounced biological activity of 5-fluorinated pyrimidines,' and the fact that the 4'-thio derivatives of various purine nucleoside analogs have been shown to retain their growth inhibitory activity against cells resistant to the corresponding ribofuranosyl analog^,^^^ the synthesis of some 4'-thio-5-halogenopyrimidine nucleosides was undertaken. These compounds were tested for the in vitro growth inhibitory activity which they exert in some tumor and bacterial cell systems. The chemical synthesis of the compounds and the results of their biological evaluation are reported in this paper. A preliminary account of these data has been given.4 Recently,l we reported that 2,9-dimethyl-6,7-benzomorphan (16), not obtainable in the usual way2 from 3-methylpyridine. could be synthesized in 12 steps from phenylace-tonitrile, only the fl isomer being formed. By some modifications of this sequence we have now prepared the 2'-hydroxy relative 18. Described below are the synthesis of 18 and the analgetic and other pharmacologic properties of 16 and 18 and two analogs, 15 and 17.
Inhibition of poly(ADP-ribose)polymerase activity by nucleoside analogs of thymidine
Biochemical Pharmacology, 1992
The pofy ADP-ribosy~ation of proteins catalyzed by poiy~ADP-ribose)polymerase (PARP) is involved in a number of important cellular metabofic activities. We evaluated various analogs of deoxythymidine and deoxyuridine as inhibitors of PARP. Most of these compounds have antiviral and/ or anticancer activities. The structural requirements for these nucieoside analogs to be inhibitors of PARP were determined. The compounds evaluated had various substitutions on the 2-, 4-and/or 5 position of the pyrimidine ring, as well as on the 2'-, 3'-and/or 5'-position of the pentose moiety. Inhibition of PARP was strongly dependent on the size of the alkyl or halogen substituent on the 5position of the pyrimidine ring. Whereas the S-position of the pyrimidine ring could be varied, alteration of the 2-or 4-position drastically decreased the inhibition of PARP. Kinetic analysis was performed with concentrations of l-10 FM NAD+. The K, values for many compounds were five to seven times lower than the K, for 3-aminobenzamide, a previously described potent inhibitor of PARP. Compounds with combined substituents at both the S-position of the pyrimidine ring and the 3'-or 5'-position of deoxyribose generaily were potent inhibitors of PARP, as for example 3'-amino-Z', 3'-dideoxy-(E)-S-(Z-bromovinyi)uridine (KS = 0.7 PM). or 5'-azido-2',S'-djdeoxy"S-ethyi~ridine flu, = 0.8,uM). The S-haIogenated analogs had K, values of IS, 35, 110 and >lOOO@M for S-iodo-2'-deoxyuridine, Sbromo-Z'-deoxyuridin~, S-chioro-Z'-deoxyuridine, and 5-fluoro-2'-deoxyuridjne, respectively, and the Salkyl analogs had K, values of 45,2.2,7,16 and 180 FM for S-methyl-Z'-deoxyuridine, 5-ethyl-2'-deoxyuridin~, 5-propyl-2'-deoxyuridine, 5-butyl-2'-deoxyuridine and 5-pentyl-2'-deoxyuridine, respectively. Twoother compounds with substituents in the 5-position of the pyrimidine moiety also had potent activities: (E)-5-(2-bromovinyl)-2'-deoxyuridinc (K, = 6pM) and 5-trifluoromethyl-2'-deoxyuridine (K, = 1.6 PM). Compounds substituted in the 2'-, 3'-and/or 5'-position of the deoxyribose moietv were investigated and S-azido-S'-deoxythymidine, .S'-amino-5'-deoxythymidine, 3'-azido-3'-deoxythymidine and 3'-deoxythymidine (d2T) had K, values of 12, 16, 18 and 3OpM, respectively.
Biochemical Pharmacology, 1987
The role of the phosphate moiety of dUMP, and some analogues, in their interaction with mammalian thymidylate synthase, has been investigated. Substrate and inhibitor activities, and the pHdependence of these activities, of dUMP and 5-FdUMP, as well as analogues with modified phosphate groups, were compared. The methyl ester of dUMP was neither a substrate nor an inhibitor. By contrast, the methyl ester of 5-FdUMP was a slow-binding inhibitor of the enzyme from L1210, Ehrlich ascites carcinoma and CCRF-CEM cells, with Ki values in the micromolar range. Both S-FdUrd and the newly synthesixed S'-me~ylphosphonate of 5-FdUrd were also slow-binding inhibitors of the Ehrlich carcinoma enzyme, but with Ir-, values in the miliimolar range. The interaction of dUMP, 5-FdUMP, and the methyl ester of the latter decreased with increase in pH, whereas that of the 5'-methyl-phosphonate of 5-FdUrd remained unchanged. The results are discussed in relation to the role of the phosphate hydroxyls of dUMP in binding to the enzyme. 5-FdUMP and its analogues exhibited differing interactions with two binding sites on the enzyme molecule, consistent with cooperativity of binding. A convenient procedure is described for the synthesis of S-fluoro-2'-deoxyuridine-5'.methylphosphonate, applicable also to the preparation of other 5'-methylphosphonate analogues.