1032-65-1Relevant articles and documents
DNA damage by ptaquiloside, a potent bracken carcinogen: Detection of selective strand breaks and identification of DNA cleavage products
Kushida, Tatsushi,Uesugi, Motonari,Sugiura, Yukio,Kigoshi, Hideo,Tanaka, Hideyuki,Hirokawa, Junichi,Ojika, Makoto,Yamada, Kiyoyuki
, p. 479 - 486 (1994)
Ptaquiloside (1) is a potent carcinogen isolated from bracken fern. Under weakly alkaline conditions, the carcinogen is converted into dienone 2 which is thought to be the ultimate agent responsible for bracken fern carcinogenicity. This study details the selective alkylation and strand scission of DNA with dienone 2. Dienone 2 forms covalent adducts through N-3 of adenine or N-7 of guanine with opening of the cyclopropyl ring. Under physiological conditions, spontaneous cleavage of the N-glycosidic linkage occurs primarily at the modified adenines to produce abasic sites. The abasic sites are so unstable that subsequent backbone breakage occurs via a β-elimination reaction. Product analyses on sequencing gels and HPLC reveal evolution of the structures of the 5'- and 3'-termini that result from the abasic sites. In addition, the sequence selectivity for the DNA cleavage is demonstrated. The cleavage rates at the target adenine residues are affected by both 5'- and 3'-flanking nucleotides. The rank orders are 5'-AT > 5'-AG > 5'-AC > 5'-AA for 3'-flanking nucleotides and 5'AA > 5'-TA > 5'-GA > 5'-CA for 5'-flanking nucleotides (where A is a site of cleavage). The most favorable sequence is estimated to be 5'-AAAT. The present results on dienone 2 have also been compared with those of CC-1065 containing a similar reactive cyclopropyl ring.
SOLID PHASE SYNTHESIS OF CYCLIC OLIGODEOXYRIBONUCLEOTIDES.
Barbato, Stefania,Napoli, Lorenzo De,Mayol, Luciano,Piccialli, Gennaro,Santacroce, Ciro
, p. 5727 - 5728 (1987)
The polymer supported synthesis of cyclic oligomers of deoxycytidilic acid is described, by a method based on an oligonucleotide-solid phase linkage through the amino group of the base.
Mechanism of activation of β-D-2′-Deoxy-2′-fluoro- 2′-C-methylcytidine and inhibition of hepatitis C virus NS5B RNA polymerase
Murakami, Eisuke,Bao, Haiying,Ramesh, Mangala,McBrayer, Tamara R.,Whitaker, Tony,Steuer, Holly M. Micolochick,Schinazi, Raymond F.,Stuyver, Lieven J.,Obikhod, Aleksandr,Otto, Michael J.,Furman, Phillip A.
, p. 503 - 509 (2007)
β-D-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (PSI-6130) is a potent specific inhibitor of hepatitis C virus (HCV) RNA synthesis in Huh-7 replicon cells. To inhibit the HCV NS5B RNA polymerase, PSI-6130 must be phosphorylated to the 5′-triphosphate form. The phosphorylation of PSI-6130 and inhibition of HCV NS5B were investigated. The phosphorylation of PSI-6130 by recombinant human 2′-deoxycytidine kinase (dCK) and uridine-cytidine kinase 1 (UCK-1) was measured by using a coupled spectrophotometric reaction. PSI-6130 was shown to be a substrate for purified dCK, with a Km of 81 μM and a kcat of 0.007 s -1, but was not a substrate for UCK-1. PSI-6130 monophosphate (PSI-6130-MP) was efficiently phosphorylated to the diphosphate and subsequently to the triphosphate by recombinant human UMP-CMP kinase and nucleoside diphosphate kinase, respectively. The inhibition of wild-type and mutated (S282T) HCV NS5B RNA polymerases was studied. The steady-state inhibition constant (Ki) for PSI-6130 triphosphate (PSI-6130-TP) with the wild-type enzyme was 4.3 μM. Similar results were obtained with 2′-C-methyladenosine triphosphate (Ki = 1.5 μM) and 2′-C-methylcytidine triphosphate (Ki = 1.6 μM). NS5B with the S282T mutation, which is known to confer resistance to 2′-C- methyladenosine, was inhibited by PSI-6130-TP as efficiently as the wild type. Incorporation of PSI-6130-MP into RNA catalyzed by purified NS5B RNA polymerase resulted in chain termination. Copyright
Tener
, p. 5,9 (1962)
Klein
, p. 164,169 (1933)
Evaluation of the role of three candidate human kinases in the conversion of the hepatitis C virus inhibitor 2′-C-methyl-cytidine to its 5′-monophosphate metabolite
Golitsina, Nina L.,Danehy Jr., Francis T.,Fellows, Ross,Cretton-Scott, Erika,Standring, David N.
, p. 470 - 481 (2010)
Nucleoside analogs are effective inhibitors of the hepatitis C virus (HCV) in the clinical setting. One such molecule, 2′-C-methyl-cytidine (2′-MeC), entered clinical development as NM283, a valine ester prodrug form of 2′-MeC possessing improved oral bioavailability. To be active against HCV, 2′-MeC must be converted to 2′-MeC triphosphate which inhibits NS5B, the HCV RNA-dependent RNA polymerase. Conversion of 2′-MeC to 2′-MeC monophosphate is the first step in 2′-MeC triphosphate production and is thought to be the rate-limiting step. Here we investigate which of three possible enzymes, deoxycytidine kinase (dCK), uridine-cytidine kinase 1 (UCK1), or uridine-cytidine kinase 2 (UCK2), mediate this first phosphorylation step. Purified recombinant enzymes UCK2 and dCK, but not UCK1, could phosphorylate 2′-MeC in vitro. However, siRNA knockdown experiments in three human cell lines (HeLa, Huh7 and HepG2) defined UCK2 and not dCK as the key kinase for the formation of 2′-MeC monophosphate in cultured human cells. These results underscore the importance of confirming enzymatic kinase data with appropriate cell-based assays. Finally, we present data suggesting that inefficient phosphorylation by UCK2 likely limits the antiviral activity of 2′-MeC against HCV. This paves the way for the use of a nucleotide prodrug approach to overcome this limitation.
Electron transfer in di(deoxy)nucleoside phosphates in aqueous solution: Rapid migration of oxidative damage (via adenine) to guanine
Candeias, Luis Pedro,Steenken, Steen
, p. 2437 - 2440 (1993)
In aqueous solution, the one-electron loss centers created statistically by the oxidant SO4.- or by photoionization in di(2′-deoxy)nucleoside phosphates (DNPs) containing the base guanine (G) become localized at G, as concluded from pulse radiolysis and 193-nm laser photolysis experiments. From the latter it is evident that, in the case of adenylyl(3′→5′)guanosine (ApG), the charge-transfer process is complete in ≤50 ns. With DNPs containing a pyrimidine and the purine base adenine, the oxidative damage is collected by the adenine moiety (k ≥ 2 × 105 s-1).
Two thymidine kinases and one multisubstrate deoxyribonucleoside kinase salvage DNA precursors in Arabidopsis thaliana
Clausen, Anders R.,Girandon, Lenart,Ali, Ashfaq,Knecht, Wolfgang,Rozpedowska, Elzbieta,Sandrini, Michael P. B.,Andreasson, Erik,Munch-Petersen, Birgitte,Piskur, Jure
, p. 3889 - 3897 (2013/01/13)
Deoxyribonucleotides are the building blocks of DNA and can be synthesized via de novo and salvage pathways. Deoxyribonucleoside kinases (EC 2.7.1.145) salvage deoxyribonucleosides by transfer of a phosphate group to the 5' of a deoxyribonucleoside. This salvage pathway is well characterized in mammals, but in contrast, little is known about how plants salvage deoxyribonucleosides. We show that during salvage, deoxyribonucleosides can be phosphorylated by extracts of Arabidopsis thaliana into corresponding monophosphate compounds with an unexpected preference for purines over pyrimidines. Deoxyribonucleoside kinase activities were present in all tissues during all growth stages. In the A. thaliana genome, we identified two types of genes that could encode enzymes which are involved in the salvage of deoxyribonucleosides. Thymidine kinase activity was encoded by two thymidine kinase 1 (EC 2.7.1.21)-like genes (AtTK1a and AtTK1b). Deoxyadenosine, deoxyguanosine and deoxycytidine kinase activities were encoded by a single AtdNK gene. T-DNA insertion lines of AtTK1a and AtTK1b mutant genes had normal growth, although AtTK1a AtTK1b double mutants died at an early stage, which indicates that AtTK1a and AtTK1b catalyze redundant reactions. The results obtained in the present study suggest a crucial role for the salvage of thymidine during early plant development. 2012 The Authors Journal compilation
