52450-18-7Relevant articles and documents
A novel synthesis and biological activity of several 5-halo-5'-amino analogues of deoxyribopyrimidine nucleosides.
Lin,Prusoff
, p. 106 - 109 (1978)
A novel synthetic procedure has been developed for the large-scale synthesis of 5-chloro-, 5-bromo-, and 5-iodo-5'-amino-2',5'-dideoxyuridine (4c-e) as well as of two new analogues, 5-iodo-5'-amino-2',5'-dideoxycytidine and 5-fluoro-5'-amino-2',5'-dideoxyuridine (4a and 4b), in good yield. The starting materials, 5-halo-2'-deoxyuridine and 5-halo-2'-deoxycytidine, are readily available and the method is straightforward. This report describes the synthesis and the biologial activities of these compounds.
Sulfur [18F]Fluoride Exchange Click Chemistry Enabled Ultrafast Late-Stage Radiosynthesis
Zheng, Qinheng,Xu, Hongtao,Wang, Hua,Du, Wen-Ge Han,Wang, Nan,Xiong, Huan,Gu, Yuang,Noodleman, Louis,Sharpless, K. Barry,Yang, Guang,Wu, Peng
, p. 3753 - 3763 (2021)
The lack of efficient [18F]fluorination processes and target-specific organofluorine chemotypes remains the major challenge of fluorine-18 positron emission tomography (PET). We report here an ultrafast isotopic exchange method for the radiosynthesis of novel PET agent aryl [18F]fluorosulfate enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully automated 18F-radiolabeling of 25 structurally and functionally diverse aryl fluorosulfates with excellent radiochemical yield (83-100%, median 98%) and high molar activity (280 GBq μmol-1) at room temperature in 30 s. The purification of radiotracers requires no time-consuming HPLC but rather a simple cartridge filtration. We further demonstrate the imaging application of a rationally designed poly(ADP-ribose) polymerase 1 (PARP1)-targeting aryl [18F]fluorosulfate by probing subcutaneous tumors in vivo.
Stereoselective Syntheses of 3-Hydroxyamino- A nd 3-Methoxyamino-2,3-Dideoxynucleosides
Bose, Sritama,Hodgson, David R. W.
, p. 9084 - 9088 (2019)
Aminonucleosides are used as key motifs in medicinal and bioconjugate chemistry; however, existing strategies toward 3-hypernucleophilic amine systems do not readily deliver deoxyribo-configured products. We report diastereoselective syntheses of deoxyribo- A nd deoxyxylo-configured 3-hydroxyamino- A nd 3-methoxyamino-nucelosides from 3-imine intermediates. The presence or absence of the 5-hydroxyl-group protection dictates facial selectivity via inter-or intramolecular delivery of hydride from BH3 (borane). Protecting group screening gave one access to previously unknown 3-methoxyamino-deoxyguanosine derivatives.
Antiviral activities of β-enantiomers of 3′-substituted-3′-deoxythymidine analogs
Faraj, Abdesslem,Alaoui, M. Abdelaziz El,Pavia, Geraldine,Gosselin, Gilles,Imbach, Jean-Louis,Schinazi, Raymond F.,Sommadossi, Jean Pierre
, p. 1287 - 1290 (1997)
Several β-L-3′-substituted-3′-deoxythymidine were stereospecifically synthesized. None of these analogs inhibited HIV-1 nor HBV replication in vitro suggesting that these β-L-pyrimidine derivatives may not be efficiently phosphorylated inside the cells Copyright
Stereochemistry of internucleoside phosphorus atom affects sugar pucker and acid hydrolysis of N3′-P5′ thio-phosphoramidates
Pourshahian, Soheil,Gryaznov, Sergei M.
, (2021)
Investigation of the sugar pucker of the two diastereomers of dinucleotide N3′-P5′-thio-phosphoramidates TNPSTNH2 and TNPSTOH shows that the Sp isomer adopts a more C3′-endo (North) sugar ring configuration than the Rp counterpart. In contrast, P-stereochemistry of oligonucleotide phosphorothioate (O3′-P5′) compounds has no effect on the nucleoside sugar puckering. This difference is also reflected in the different rate of acid hydrolysis for the two isomers. Thus, the Rp stereoisomer with less prevalent C3′-endo configuration has an acid hydrolysis rate constant ~50% higher than that of the Sp molecule. The TNPOTNH2 and TNPOTOH dinucleotides are hydrolyzed an order of magnitude faster than TNPSTNH2 and TNPSTOH, respectively. In addition, dinucleotides with the terminal 3′-OH group are hydrolyzed two times faster than their 3′-NH2 counterparts.
1,3-Dipolar cycloaddition of alkenes to 3'-azido-3'-deoxythymidine as a route to 3'-deoxythymidin-3'-yl derivatives
Solyev, Pavel N.,Novikov, Roman A.,Kukhanova, Marina K.,Jasko, Maxim V.
, p. 206 - 208 (2014)
1,3-Cycloaddition of acrylonitrile, acrylamide, vinyl acetate and allyl alcohol to azido group of 3'-azido-3'-deoxythymidine under mild conditions afforded the corresponding adducts which were tested as inhibitors of HIV reverse transcriptase.
Probing the binding requirements of modified nucleosides with the dna nuclease snm1a
Dürr, Eva-Maria,McGouran, Joanna F.
, (2021/06/21)
SNM1A is a nuclease that is implicated in DNA interstrand crosslink repair and, as such, its inhibition is of interest for overcoming resistance to chemotherapeutic crosslinking agents. However, the number and identity of the metal ion(s) in the active site of SNM1A are still unconfirmed, and only a limited number of inhibitors have been reported to date. Herein, we report the synthesis and evaluation of a family of malonate-based modified nucleosides to investigate the optimal positioning of metal-binding groups in nucleoside-derived inhibitors for SNM1A. These compounds include ester, carboxylate and hydroxamic acid malonate derivatives which were installed in the 5′-position or 3′-position of thymidine or as a linkage between two nucleosides. Evaluation as inhibitors of recombinant SNM1A showed that nine of the twelve compounds tested had an inhibitory effect at 1 mM concentration. The most potent compound contains a hydroxamic acid malonate group at the 5′-position. Overall, our studies advance the understanding of requirements for nucleoside-derived inhibitors for SNM1A and indicate that groups containing a negatively charged group in close proximity to a metal chelator, such as hydroxamic acid malonates, are promising structures in the design of inhibitors.
Selective Inhibition of DNA Polymerase β by a Covalent Inhibitor
Yuhas, Shelby C.,Laverty, Daniel J.,Lee, Huijin,Majumdar, Ananya,Greenberg, Marc M.
supporting information, p. 8099 - 8107 (2021/06/21)
DNA polymerase β (Pol β) plays a vital role in DNA repair and has been closely linked to cancer. Selective inhibitors of this enzyme are lacking. Inspired by DNA lesions produced by antitumor agents that inactivate Pol β, we have undertaken the development of covalent small-molecule inhibitors of this enzyme. Using a two-stage process involving chemically synthesized libraries, we identified a potent irreversible inhibitor (14) of Pol β (KI = 1.8 ± 0.45 μM, kinact = (7.0 ± 1.0) × 10-3 s-1). Inhibitor 14 selectively inactivates Pol β over other DNA polymerases. LC-MS/MS analysis of trypsin digests of Pol β treated with 14 identified two lysines within the polymerase binding site that are covalently modified, one of which was previously determined to play a role in DNA binding. Fluorescence anisotropy experiments show that pretreatment of Pol β with 14 prevents DNA binding. Experiments using a pro-inhibitor (pro-14) in wild type mouse embryonic fibroblasts (MEFs) indicate that the inhibitor (5 μM) is itself not cytotoxic but works synergistically with the DNA alkylating agent, methylmethanesulfonate (MMS), to kill cells. Moreover, experiments in Pol β null MEFs indicate that pro-14 is selective for the target enzyme. Finally, pro-14 also works synergistically with MMS and bleomycin to kill HeLa cells. The results suggest that pro-14 is a potentially useful tool in studies of the role of Pol β in disease.
Thiourea Modified Doxorubicin: A Perspective pH-Sensitive Prodrug
Krasnovskaya, Olga O.,Malinnikov, Vladislav M.,Dashkova, Natalia S.,Gerasimov, Vasily M.,Grishina, Irina V.,Kireev, Igor I.,Lavrushkina, Svetlana V.,Panchenko, Pavel A.,Zakharko, Marina A.,Ignatov, Pavel A.,Fedorova, Olga A.,Jonusauskas, Gediminas,Skvortsov, Dmitry A.,Kovalev, Sergey S.,Beloglazkina, Elena K.,Zyk, Nikolay V.,Majouga, Alexander G.
, p. 741 - 750 (2019/03/02)
A novel approach to the synthesis of pH-sensitive prodrugs has been proposed: thiourea drug modification. Resulting prodrugs can release the cytotoxic agent and the biologically active 2-thiohydantoin in the acidic environment of tumor cells. The concept of acid-catalyzed cyclization of thioureas to 2-thiohydantoins has been proven using a FRET model. Dual prodrugs of model azidothymidine, cytotoxic doxorubicin, and 2-thiohydantoin albutoin were obtained, which release the corresponding drugs in the acidic environment. The resulting doxorubicin prodrug was tested on prostate cancer cells and showed that the thiourea-modified prodrug is less cytotoxic (average IC50 ranging from 0.5584 to 0.9885 μM) than doxorubicin (IC50 ranging from 0.01258 to 0.02559 μM) in neutral pH 7.6 and has similar toxicity (average IC50 ranging from 0.4970 to 0.7994 μM) to doxorubicin (IC50 ranging from 0.2303 to 0.8110 μM) under mildly acidic conditions of cancer cells. Cellular and nuclear accumulation in PC3 tumor cells of Dox prodrug is much higher than accumulation of free doxorubicin.
5′-silylated 3′-1,2,3-triazolyl thymidine analogues as inhibitors of West Nile Virus and Dengue virus
Vernekar, Sanjeev Kumar V.,Qiu, Li,Zhang, Jing,Kankanala, Jayakanth,Li, Hongmin,Geraghty, Robert J.,Wang, Zhengqiang
, p. 4016 - 4028 (2015/05/27)
West Nile virus (WNV) and Dengue virus (DENV) are important human pathogens for which there are presently no vaccine or specific antivirals. We report herein a 5′-silylated nucleoside scaffold derived from 3′-azidothymidine (AZT) consistently and selectively inhibiting WNV and DENV at low micromolar concentrations. Further synthesis of various triazole bioisosteres demonstrated clear structure-activity relationships (SARs) in which the antiviral activity against WNV and DENV hinges largely on both the 5′-silyl group and the substituent of 3′-triazole or its bioisosteres. Particularly interesting is the 5′ silyl group which turns on the antiviral activity against WNV and DENV while abrogating the previously reported antiviral potency against human immunodeficiency virus (HIV-1). The antiviral activity was confirmed through a plaque assay where viral titer reduction was observed in the presence of selected compounds. Molecular modeling and competitive S-adenosyl-l-methionine (SAM) binding assay suggest that these compounds likely confer antiviral activity via binding to methyltransferase (MTase).
