3258-07-9Relevant academic research and scientific papers
Enantioselective synthesis and biological evaluation of 5-o-carboranyl pyrimidine nucleosides
Mourier, Nicolas S.,Eleuteri, Alessandra,Hurwitz, Selwyn J.,Tharnish, Phillip M.,Schinazi, Raymond F.
, p. 2759 - 2766 (2007/10/03)
Base-modified carborane-containing nucleosides such as 5-o-carboranyl-2'-deoxyuridine (CDU) when combined with neutrons have potential for the treatment of certain malignancies. Lack of toxicity in various cells, high accumulation in cancer cells and intracellular phosphorylation are desirable characteristics for modified nucleosides used in boron neutron capture therapy (BNCT) for brain tumors and other malignancies. The aim of this work was to synthesize the two β-enantiomers of several 5-o-carboranyl-containing nucleosides. These derivatives may possess favorable properties such as high lipophilicity, high transportability, the ability to be phosphorylated, and resistance to catabolism. β-Isomers of 2',3'-dihydroxynucleosides and analogues containing a heteroatom in the sugar moiety were also synthesized. Carboranyl pyrimidine nucleosides were prepared either from the parent β-D-nucleoside, β-L-nucleoside, or by a coupling reaction. The dioxolane derivative 7Scheme 1Reagents and conditions: (a) 1,1,1,3,3,3-hexamethydisilazane, ammonium sulfate, reflux, 6 h; (b) tin(IV) chloride, CH2Cl2, 0°C, 2h; (c) tetrabutylammonium fluoride, 1 M sol in THF, 0°C, 3h. was prepared by a coupling reaction between protected 5-o-carboranyluracil (8, CU) and the corresponding protected heterocycle. Specific catalysts were used during the N-glycosylation process to favor the formation of the β-isomer. Biological evaluation of these new chiral 5-o-carboranyl pyrimidine derivatives indicated that most of these compounds have low toxicity in a variety of normal and malignant cells and achieved high cellular levels in a lymphoblastoid cell line. Increasing the number of hydroxyl groups on the sugar moiety decreased the cellular accumulation and serum binding to different extents. Five compounds were identified for further biological evaluation as potential agents for BNCT. Copyright (C) 1999 Elsevier Science Ltd.
Synthesis of Several Pyrimidine L-Nucleoside Analogues as Potential Antiviral Agents
Lin, Tai-Shun,Luo, Mei-Zhen,Liu, Mao-Chin
, p. 1055 - 1068 (2007/10/02)
β-L-5-Iodo-2'-deoxyuridine (β-L-IUdR, 7) and 1-uracil (β-L-BV-ara-U, 10) have been synthesized via a multi-step synthesis from L-arabinose. 2',3'-Dideoxy-β-L-5-azacytidine (18), 2',3'-dideoxy-β-L-2-thiocytidine (20) and their respective α-anomers, compounds 19 and 21, also were synthesized by direct coupling of 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (13) with the corresponding silylated bases, in the presence of EtAlCl2 in CH2Cl2, followed by separation of the α- and β-isomers and deblocking of the 5'-protecting groups.In addition, 2',3'-dideoxy-β-L-5-fluorocytidine (34), a potent anti-HIV and anti-HBV agent, was synthesized by an alternative methodology from 2',3'-dideoxy-β-L-5-fluorouridine (31) via a 4-triazolylpyrimidinone intermediate.These L-nucleoside analogues were tested in vitro against HIV, HBV, HSV-1, and HSV-2.Among these compounds, 2',3'-dideoxy-β-L-5-azacytidine (18) was found to show significant activity against HBV in vitro at approximately the same level as 2',3'-dideoxy-β-D-cytidine (ddC), which is a known potent anti-HBV agent.
Synthesis of 1-β-L-arabinofuranosylcytosine (β-L-Ara-C) and 2'-deoxy- 2'-methylene-β-L-cytidine (β-L-DMDC) as potential antineoplastic agents
Lin,Luo,Liu
, p. 1861 - 1870 (2007/10/02)
1-β-L-Arabinofuranosylcytosine (β-L-Ara-C, 7) and 2'-deoxy-2'-methylene- β-L-cytidine (β-L-DMDC, 14) have been synthesized via a multi-step synthesis from L-arabinose. These compounds were tested in vitro against L1210, P388, Sarcoma 180, and CEM cells, and found not to be active at a concentration up to 100 μM. β-L-Ara-C and β-L-DMDC were also tested against HSV-1 and HSV-2 and yielded ID50 values of >100 μM.
Ionization of purine nucleosides and nucleotides and their components by 193-nm laser photolysis in aqueous solution: Model studies for oxidative damage of DNA 1
Candeias,Steenken
, p. 699 - 704 (2007/10/02)
The effect of 20-ns pulses of 193-nm laser light on aqueous solutions of purine bases, (2′-deoxy)nucleosides, and (2′-deoxy)nucleotides was investigated, and monophotonic ionization was observed. Although (deoxy)ribose and (deoxy)ribose phosphates are also ionized by 193-nm light, the photoionization of the (deoxy)nucleosides and -tides takes place predominantly (90%) at the purine moiety, due to the much higher extinction coefficients at 193 nm of the bases as compared to the (deoxy)ribose phosphates. The quantum yields of photoionization (φPl) of the purines are in the range 0.01 to 0.08, based on φ(Cl-) at 193 nm of 0.46. As shown by comparison with data obtained from pulse radiolysis, the ionized purines, i.e., the radical cations, deprotonate in neutral solution, yielding neutral radicals. The radical cation of 1-methylguanosine, produced by photoionization in oxygen-saturated aqueous solution, deprotonates with the rate constant 3.5 × 105 s-1. In the absence of oxygen, the hydrated electrons resulting from the photoionization react with the untransformed purine derivatives to yield the corresponding radical anions. As these are rapidly protonated by water (as concluded from pulse radiolysis), the photoionization in deaerated neutral solution results in two different neutral radicals: a deprotonated radical cation and a protonated radical anion.
Hydrolysis of Tosyl Esters Initiated by an Electron Transfer from Photoexcited Electron-Rich Aromatic Compounds
Nishida, Atsushi,Hamada, Tatsuo,Yonemitsu, Osamu
, p. 3386 - 3387 (2007/10/02)
Selective hydrolysis of tosyl esters was realized by irradiation of Uv light (>300 nm) in the presence of electron-rich aromatic compounds and the reaction proceeds via en electron-transfer process.
Aqueous conversion kinetics and mechanisms of ancitabine, a prodrug of the antileukemic agent cytarabine
Kirsch,Notari
, p. 896 - 902 (2007/10/02)
The kinetics of conversion of the prodrug ancitabine to the anti-cancer drug cytarabine have been studied in aqueous solutions in the pH range of 1.5-10.7, temperature range of 19.5-80.0°C, ionic strength range of 10-4 to 1.5, and in the presence of several general-base catalysts. Under all conditions ancitabine was quantitatively converted to cytarabine. The pH-rate profiles were linear with slope = 1 in alkaline pH, becoming pH independent in the region of maximum stability at pH ≤4, where buffer catalysis was found to be insignificant and k(obs) ? (1.12 x 1011 h-1)·exp {-10121 deg/T}. At 30°C, pH ≤4, it is calculated that an aqueous ancitabine solution will maintain 90% of its initial concentration for 12 d. A novel method for measuring general-base catalysis in competition with predominating a specific-base catalysis and in the presence of secondary salt effects a constant ionic strength was developed. Three mechanisms of hydrolytic prodrug conversion are proposed: nucleophilic hydroxide addition, general base-assisted nucleophilic water attack, and spontaneous water attack.
