25526-93-6Relevant articles and documents
Synthesis and antiviral (HIV-1, HBV) activities of 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'-deoxythymidine diastereomers. Potential prodrugs to 3'-fluoro-3'-deoxythymidine
Kumar,Wang,Wiebe,Knaus
, p. 3554 - 3560 (1994)
A new class of 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'- deoxythymidines (4-13) were investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodrugs to 3'-fluoro-3'- deoxythymidine (FLT), were designed to have properties which would enhance their duration of action, lipophilicity, and cephalic delivery to the central nervous system. The 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'- deoxythymidines, which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, Cl, I; R = OMe, N3) to the 5,6-olefinic bond of FLT. These 5-halo-6-methoxy-5,6-dihydro derivatives are more lipophilic (P = 1.5-5.15 range) than the parent compound FLT (P = 0.5). Regeneration of the 5,6-olefinic bond to give FLT, upon incubation of the 5-halo-6-methoxy-5,6-dihydro compounds with glutathione, was dependent on the nature of the 5-halo substituent (I > Br > Cl). The ability of these 5-halo-6-methoxy(or azido)-5,6-dihydro compounds (4-13) to protect CEM cells against HIV-induced cytopathogenicity was evaluated. The C- 5 halo substituent was a determinant of anti-HIV-1 activity where the approximately equipotent 5-iodo and 5-bromo were generally more potent than the 5-chloro derivatives of FLT. Compounds having the (5S,6S)-configuration were more potent than the corresponding (5R,6R)-diastereomer. The most potent anti-HIV-1 agents, which included the (5R,6R)-5-Br,6-OMe (4), (5S,6S)-5- Br,6-OMe (5), and (5S,6S)-5-I,6-OMe (10) derivatives of FLT, exhibited comparable activities to the reference drugs AZT and FLT. Although (5R,6R)- 5-bromo-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine (4) inhibited hepatitis B virus replication at a 5-6-fold higher concentration (EC50) than the reference drug 2',3'-dideoxycytidine (DDC), it was 3-5-fold less cytotoxic (CC50) than DDC.
Radiolabeled cyclosaligenyl monophosphates of 5-iodo-2′-deoxyuridine, 5-iodo-3′-fluoro-2′,3′-dideoxyuridine, and 3′-fluorothymidine for molecular radiotherapy of cancer: Synthesis and biological evaluation
Kortylewicz, Zbigniew P.,Kimura, Yu,Inoue, Kotaro,MacK, Elizabeth,Baranowska-Kortylewicz, Janina
supporting information; experimental part, p. 2649 - 2671 (2012/06/16)
Targeted molecular radiotherapy opens unprecedented opportunities to eradicate cancer cells with minimal irradiation of normal tissues. Described in this study are radioactive cyclosaligenyl monophosphates designed to deliver lethal doses of radiation to cancer cells. These compounds can be radiolabeled with SPECT- and PET-compatible radionuclides as well as radionuclides suitable for Auger electron therapies. This characteristic provides an avenue for the personalized and comprehensive treatment strategy that comprises diagnostic imaging to identify sites of disease, followed by the targeted molecular radiotherapy based on the imaging results. The developed radiosynthetic methods produce no-carrier-added products with high radiochemical yield and purity. The interaction of these compounds with their target, butyrylcholinesterase, depends on the stereochemistry around the P atom. IC50 values are in the nanomolar range. In vitro studies indicate that radiation doses delivered to the cell nucleus are sufficient to kill cells of several difficult to treat malignancies including glioblastoma and ovarian and colorectal cancers.
Synthesis and Antiviral Activity of Novel Fluorinated 2′,3′ -Dideoxynucleosides
Kumar, Piyush,Ohkura, Kazue,Balzarini, Jan,De Clercq, Erik,Seki, Koh-Ichi,Wiebe, Leonard I.
, p. 7 - 29 (2007/10/03)
A series of 5-(trifluoroethoxymethyl)-2′,3′-dideoxyuridines and 5-[bis(trifluormethoxy)-methyl]-2′,3′-dideoxyuridines have been prepared and screened for antiviral activity. The conformations of these compounds are discussed on the bases of NOE studies and the MO calculations. Modelling and NOE studies suggest both syn- and anti conformations for these 5-(2,2,2-trifluoroethoxymethyl)- and 5-[bis(2,2,2-trifluoroethoxy)-methyl]-derivatives. The NOE parameters are also suggested to be more attributable to the nature of the fluorine atom than to structural or conformational changes. Compounds 17, 26 and 30 showed some activity in anti-HIV-1 and anti-HIV-2 assays, but the compounds were devoid of activity against HSV and human rhinovirus. The compounds tested exhibited low cytotoxicity and were inactive against a bank of cancer cells in vitro.
