175013-49-7Relevant academic research and scientific papers
Nucleosides and nucleotides. 176. 2'-Deoxy-2'-hydroxylaminocytidine: A new antitumor nucleoside that inhibits DNA synthesis although it has a ribonucleoside structure
Ogawa, Akira,Shuto, Satoshi,Inanami, Osamu,Kuwabara, Mikinori,Tanaka, Motohiro,Sasaki, Takuma,Matsuda, Akira
, p. 1913 - 1918 (1998)
The design and synthesis of potential antitumor antimetabolites 2'- deoxy-2'-hydroxylaminouridine (2'-DHAU) and -cytidine (2'-DHAC) are described. We found that 2'-DHAC in neutral solution generated 2'-aminoxy radicals at room temperature. 2'-DHAC inhibited the growth of L1210 and KB cells, with IC50 values of 1.58 and 1.99 μM, respectively, more potently than 2'-DHAU, with IC50 values of 34.5 and 27.3 μM, respectively. 2'-DHAC was effective against 9 human cell lines, with IC50 values in the micromolar range. The in vivo antitumor activity of 2'-DHAC was also examined using the mouse leukemia P388 model, which gave a T/C value of 167%. Phosphorylation of 2' -DHAC by uridine/cytidine kinase was essential for its cytotoxicity, as suggested by a competition experiment using several common nucleosides. Inhibition of DNA synthesis was the predominant mechanism of action of 2'-DHAC, although it has a ribo-configuration.
Nucleosides and nucleotides. 180. Synthesis and antitumor activity of nucleosides that have a hydroxylamino group instead of a hydroxyl group at the 2'- or 3'-position of the sugar moiety
Ogawa, Akira,Tanaka, Motohiro,Sasaki, Takuma,Matsuda, Akira
, p. 5094 - 5107 (2007/10/03)
The design and synthesis of potential antitumor antimetabolites 2'- deoxy-2'-(hydroxylamino)uridine (15), -cytidine (19, 2'-DHAC), and -adenosine (35), their regioisomers, 3'-deoxy-3'-(hydroxylamino)uridine (40) and - cytidine (45, 3'-DHAC), and their 2'-deoxy analogues, 2',3'-dideoxy-3'- (hydroxylamino)uridine (49) and -cytidine (52, 3'-dDHAC), are described. We measured the pK(a) values of the hydroxylamino group in 15 and 40 using 13C NMR spectroscopy as a function of pH to be 2.9 and 3.4, respectively. We also found that these nucleosides gradually decomposed in neutral solution but not in acidic solution. This decomposition may be related to the generation of aminoxy radicals at the sugar moiety. The in vitro cytotoxicity of these nucleosides was evaluated using L1210 and KB cells. 2'-DHAC (19) inhibited the growth of L1210 and KB cells, with IC50 values of 1.58 and 1.99 μM, respectively. 3'-DHAC (45) and 3'-dDHAC (52) were also cytotoxic against L1210 cells, with IC50 values of 4.03 and 1.84 μM, respectively, but not against KB cells. The cytotoxicity of 2'-DHAC (19) and 3'-DHAC (45) against L1210 cells in vitro was reversed by the addition of cytidine, while that of 3'-dDHAC (52) was reversed by 2'-deoxycytidine. 2'-DHAC (19) and 3'-dDHAC (52) mainly inhibited DNA synthesis in L1210 cells, while 3'-DHAC (45) inhibited RNA synthesis. We also evaluated the antitumor activities of 2'- DHAC (19) and 3'-DHAC (45) against murine Meth-A fibrosarcoma cells in vivo. 2'-DHAC (19) was more active than 3'-DHAC (45) when administered intravenously on days 1-10 consecutively at 10 mg/kg/day. 2'-DHAC (19) inhibited tumor growth at a rate of 66.9%.
2'-Deoxy-2'-alkoxyaminouridines: Novel 2'-substituted uridines prepared by intramolecular nucleophilic ring opening of 2,2'-O-anhydrouridines
Sebesta, David P.,O'Rourke, Sarah S.,Martinez, Rogelio L.,Pieken, Wolfgang A.,McGee, Danny P. C.
, p. 14385 - 14402 (2007/10/03)
Natural and unnatural modified nucleosides and nucleotides play important roles in biology, medicine, and as biomedical research tools. Reported herein is an application of synthetic methodology developed for the stereo- and regiospecific introduction of structural modifications at the 2'-position of uridine nucleosides. A novel class of modified nucleosides, 2'-alkoxylamino-2'-deoxy uridines, are prepared by intramolecular nucleophilic addition of a 3'-tethered alkoxycarbamate nucleophile to the 2'-position with concomitant opening of a 2,2'-anhydrouridine.
