70255-96-8Relevant articles and documents
Modified 5'-Trityl Nucleosides as Inhibitors of Plasmodium falciparum dUTPase
Ruda, Gian Filippo,Nguyen, Corinne,Ziemkowski, Przemyslaw,Felczak, Krzysztof,Kasinathan, Ganasan,Musso-Buendia, Alexander,Sund, Christian,Zhou, Xiao Xiong,Kaiser, Marcel,Ruiz-Perez, Luis M.,Brun, Reto,Kulikowski, Tadeusz,Johansson, Nils Gunnar,Gonzalez-Pacanowska, Dolores,Gilbert, Ian H.
experimental part, p. 309 - 320 (2012/01/12)
2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base. Compounds were tested against both the enzyme and the parasite. Variations of the 5'-trityl group and of the 3'-substituent were well tolerated and yielded active compounds. However, there is a clear requirement for the uracil base for activity, because modifications of the uracil ring result in loss of enzyme inhibition and significant decreases in antiplasmodial action. Fewer trips to the dUMP: dUTPase is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this P.falciparum enzyme. Herein we report further structure-activity studies of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base.
Synthesis of pyrimidine 2′-deoxy ribonucleosides branched at the 2′-position via radical atom-transfer cyclization reaction with a vinylsilyl group as a radical-acceptor tether
Sukeda,Shuto,Sugimoto,Ichikawa,Matsuda
, p. 8988 - 8996 (2007/10/03)
Recently, we developed a regio- and stereoselective method for introducing a vinyl group at the position β to a hydroxyl group in halohydrins or α-phenylselenoalkanols via a radical atom-transfer cyclization reaction with a vinylsilyl group as a temporary connecting radical-acceptor tether. The synthesis of 2′-deoxy-2′-C-vinyl- and 2′-deoxy-2′-C-hydroxymethyluridines (7 and 8, respectively) and the corresponding 2′-deoxycytidine congeners (10 and 11, respectively), which were designed as potential antitumor and/or antiviral agents, was achieved using this radical atom-transfer cyclization as the key step. When the 2′-deoxy-2′-iodo-5′-O-monomethoxytrityl (MMTr) uridine derivative 19a, bearing a vinylsilyl group at the 3′-hydroxyl group, was heated with (Me3Sn)2 and AIBN in benzene, the corresponding radical atom-transfer product was generated, which in turn was successively treated with tetrabutylammonium fluoride and TBSCI/imidazole to give the desired 2′-deoxy-5′-O-MMTr-3′-O-TBS-2′-C-vinyluridine (25). Compound 25 was successfully converted into the target 2′-deoxy-2′-branched pyrimidine ribonucleosides 7, 8, 10, and 11.
