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1.
Marie Hamann Claire Pierra Jean-Pierre Sommadossi Chiara Musiu Luana Vargiu Michel Liuzzi Richard Storer Gilles Gosselin 《Bioorganic & medicinal chemistry》2009,17(6):2321-2326
Several thieno[3,4-d]pyrimidine derivatives, including four hitherto unknown 2′,3′-dideoxy- and 2′,3′-dideoxy-2′,3′-didehydro-C-nucleoside analogues of adenosine and inosine have been synthesized. When evaluated in cell culture experiments against human immunodeficiency virus, none of the tested compounds exhibited any significant antiviral effect, while two of them showed some cytotoxicity. 相似文献
2.
P. Franchetti L. Cappellacci G. Cristalli M. Grifantini A. Pani P. La Colla 《Nucleosides, nucleotides & nucleic acids》2013,32(7):1551-1562
Abstract - The 4-amino-1-(2.3-dideoxy-β-D-glycero-pent-2-enofurano-syl)-1H-irnidazo[4,5-c]pyridine (1) and 4-amino-1-(2,3-dideoxy-β-D-gfycero-pentofuranosyl)-1H-imidazo[4,5-c]pyridine (2), 3-deaza analogues of the anti-HIV agents 2′.3′-didehydro-2′,3′-dideoxyadenosine (d4A) and 2′,3′-dideoxy-adenosine (ddA), have been synthesized. The reaction of 3-deazaadenosine (3) with 2-acetoxyisobutyryl bromide yielded a mixture of cis and trans 2′,3′-ha-lo acetates which was convertcd into olefinic nucleoside (1) on treatment with a Zn/Cu couplc and then with methanolic ammonia. The 2′,3′-dideoxy-3-deazaadenosine (2) was obtained by catalytic reduction of 1. A number of phosphate triester derivatives of 2 have also been prepared. The diethyl-, dipropyl- and dibutylpliospliates 7a-c and 3-deazaadenosine have shown anti-HIV activity at non-cytotoxic doses. Compounds 7a-c have also shown significant cytostatic activity against murine colon adenocarcinoma cells. 相似文献
3.
Yutaka Kubota Nobuhide Ishizaki Kazuhiro Haraguchi Takayuki Hamasaki Masanori Baba Hiromichi Tanaka 《Bioorganic & medicinal chemistry》2010,18(20):7186-7192
Synthesis of the 4′-ethynyl and 4′-cyano phosphonates 8–11, which mimic the 5′-monophosphate of 4′-branched 2′,3′-didehydro-2′,3′-dideoxy nucleosides, was investigated by employing the 3′,4′-unsaturated nucleosides (13 and 28) as the starting material. The synthesis was initiated by the electrophilic addition of NIS/(EtO)2P(O)CH2OH to these unsaturated nucleosides. After introduction of the 2′,3′-double bond, the 4′-hydroxylmethyl group of the resulting adducts was transformed into the ethynyl or cyano group. While the 4′-cyano phosphonates 9 and 11 were not sufficiently stable to be isolated, the 4′-ethynyl counterparts (8 and 10) were obtained as their mono-ammonium salts. The adenine derivative 8 showed almost comparable anti-HIV-1 activity to that of d4T. 相似文献
4.
Whi-Gun Chae 《Biotechnology and Bioprocess Engineering》1999,4(1):17-20
Facile synthetic methods of 2′,5′-dideoxy-, 2′,3′-dideoxy- and 3′-deoxy-1,N
6-ethenoadenosine nucleosides by either an enzymatic dideoxyribosyl transfer reaction or a simple chemical reaction were proposed.
The synthetic products were isolated and purified by preparative HPLC and their structures were confirmed by1H NMR (500 MHz) and FAB-MS including high resolution mass measurement. These modified nucleoside analogs have not been reported
yet. Therefore, these modified nucleoside analogs are of potential value to be studied further for biological activity such
as anticancer or antiviral. 相似文献
5.
Hong-wang Zhang Steven J. Coats Lavanya Bondada Franck Amblard Mervi Detorio Ghazia Asif Emilie Fromentin Sarah Solomon Aleksandr Obikhod Tony Whitaker Nicolas Sluis-Cremer John W. Mellors Raymond F. Schinazi 《Bioorganic & medicinal chemistry letters》2010,20(1):60-64
Based on the promising drug resistance profile and potent anti-HIV activity of β-d-3′-azido-2′,3′-dideoxyguanosine, a series of purine modified nucleosides were synthesized by a chemical transglycosylation reaction and evaluated for their antiviral activity, cytotoxicity, and intracellular metabolism. Among the synthesized compounds, several show potent and selective anti-HIV activity in primary lymphocytes. 相似文献
6.
Saúl Martínez-Montero Susana Fernández Yogesh S. Sanghvi Emmanuel A. Theodorakis Mervi A. Detorio Tamara R. Mcbrayer Tony Whitaker Raymond F. Schinazi Vicente Gotor Miguel Ferrero 《Bioorganic & medicinal chemistry》2012,20(23):6885-6893
A series of 2′,3′-dideoxy-2′,2′-difluoro-4′-azanucleosides of both pyrimidine and purine nucleobases were synthesized in an efficient manner starting from commercially available L-pyroglutamic acid via glycosylation of difluorinated pyrrolidine derivative 15. Several 4′-azanucleosides were prepared as a separable mixture of α- and β-anomers. The 6-chloropurine analogue was obtained as a mixture of N7 and N9 regioisomers and their structures were identified based on NOESY and HMBC spectral data. Among the 4′-azanucleosides tested as HIV-1 inhibitors in primary human lymphocytes, four compounds showed modest activity and the 5-fluorouracil analogue (18d) was found to be the most active compound (EC50 = 36.9 μM) in this series. None of the compounds synthesized in this study demonstrated anti-HCV activity. 相似文献
7.
Wonsuk Chang Jinfa Du Suguna Rachakonda Bruce S. Ross Serge Convers-Reignier Wei T. Yau Jean-Francois Pons Eisuke Murakami Haiying Bao Holly Micolochick Steuer Phillip A. Furman Michael J. Otto Michael J. Sofia 《Bioorganic & medicinal chemistry letters》2010,20(15):4539-4543
Hepatitis C virus afflicts approximately 180 million people worldwide and currently there are no direct acting antiviral agents available to treat this disease. Our first generation nucleoside HCV inhibitor, RG7128 has already established proof-of-concept in the clinic and is currently in phase IIb clinical trials. As part of our continuing efforts to discover novel anti-HCV agents, 3′,4′-oxetane cytidine and adenosine nucleosides were prepared as inhibitors of HCV RNA replication. These nucleosides were shown not to be inhibitors of HCV as determined in a whole cell subgenomic replicon assay. However, 2′-mono/diflouro analogs, 4, 5, and 6 were readily phosphorylated to their monophosphate metabolites by deoxycytidine kinase and their triphosphate derivatives were shown to be inhibitors of HCV NS5B polymerase in vitro. Lack of anti-HCV activity in the replicon assay may be due to the inability of the monophosphates to be converted to their corresponding diphosphates. 相似文献
8.
Jean-Christophe G. Graciet Junxing Shi Raymond F. Schinazi 《Nucleosides, nucleotides & nucleic acids》2013,32(4):711-727
Abstract The four isomers of the 5-o-carboranyl-2′,3′-didehydro-2′,3′-dideoxyuridine (d4CU) were synthesized and their antiviral activity and cytotoxicity in normal and cancer human cells determined. Coupling of silylated 5-o-carboranyluracil with the protected D/L 2,3-dideoxy-2-phenylselenenylribosylacetates provided after oxidative elimination and deprotection, the desired compounds. The presence of the electron deficient 5-o-carboranyl moiety on uracil influenced the yield of the various isomers. In general, the compounds demonstrated weak anti-human immunodeficiency virus activity in primary human lymphocytes. No marked difference in the biological profile was noted for the various optical isomers, suggesting that the high lipophilicity of these nucleosides imparted by the carboranyl moiety overrides stereochemical considerations in the 2′,3′-didehydro-2′,3′-dideoxy-aglycon moiety. 相似文献
9.
Victor E. Marquez Lak S. Jeong Marc C. Nicklaus Cliff George 《Nucleosides, nucleotides & nucleic acids》2013,32(3-5):555-558
Abstract The efficient DAST fluorination of deoxy-4′-thiopyrimidine nucleosides is reported. The cytidine analogue 3b was marginally effective against HIV. 相似文献
10.
Nicolas Mourier Michel Camplo Giovanna Schioppacassi Della Bruna Francesco Pellacini Domenico Ungheri Jean-Claude Chermann 《Nucleosides, nucleotides & nucleic acids》2013,32(7):1057-1091
Abstract A series of anti-HIV prodrugs possessing various polyaminated side arms have been developed. The incorporation of a N-Boc protected monoamine or diamine side arm into the backbone of the 2′,3′-dideoxy-3′-thiacytidine 1 (BCH-189) provided an increase in antiviral potency, which could be several orders magnitude greater than the parent drug (1) depending on the cell culture systems used (MT-4 or MDMs). Twenty six 2′,3′-dideoxy-3′-thiacytidine prodrugs which differ from each other by the length, the nature of the 5′-O function and the 5′-O or /and N-4 position on the nucleoside moiety were synthesized. Among this new series of prodrugs, several congeners (12c and 12a) were found to inhibit HIV-1 replication in cell culture with 50% effective concentrations ECso of 10 and 50 nM respectively, in MT-4 cells. Compound 12c was found more active on infected MDMs cells with 50% effective concentration of 0.01 nM. The synthesis and the antiviral properties of these compounds are discussed. 相似文献
11.
Panagiotis Ioannidis Björn Classon Bertil Samuelsson Ingemar Kvarnström 《Nucleosides, nucleotides & nucleic acids》2013,32(5):449-462
Abstract 1-(2,3-Dideoxy-2-C-hydroxymethyl-β-D-threo-pentofuranosyl)-, 1-(2,3-didehydro-2,3-dideoxy-2-C-hydroxymethyl-β-D-glycero-pentofuranosyl)- and 1-(2-C-azidomethyl-2,3-didehydro-2,3-dideoxy-β-D-glycero-pentofuranosyl)uracuracil, thymine and cytosine were synthesized and evaluated for their anti-HIV activities. A key step of the synthesis involves a novel alcohol transposition of2-methylene-nucleoside analogues. 相似文献
12.
Galina V. Zaitseva Evgenii I. Kvasyuk Elena V. Vaaks Vladimir N. Barai Sergei B. Bokut Anatolii I. Zinchenko 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):819-834
Abstract Treatment of O2, 3′-anhydro-5′-O-trityl derivatives of thymidine (1) and 2′-deoxyuridine (2) with lithium azide in dimethylformamide at 150 °C resulted in the formation of the corresponding isomeric 3′-azido-2′, 3′-dideoxy-5′-O-trityl-β-D-ribofuranosyl N1- (the major products) and N3-nucleosides (3/4 and 5/6). 3′-Amino-2′, 3′-dideoxy-β-D-ribofuranosides of thymidine [Thd(3′NH2)], uridine [dUrd(3′NH2)], and cytidine [dCyd(3′NH2)] were synthesized from the corresponding 3′-azido derivatives. The Thd(3′NH2) and dUrd(3′NH2) were used as donors of carbohydrate moiety in the reaction of enzymatic transglycosylation of adenine and guanine to afford dAdo(3′NH2) and dGuo(3′NH2). The substrate activity of dN(3′NH2) vs. nucleoside phosphotransferase of the whole cells of Erwinia herbicola was studied. 相似文献
13.
Zhe Chen Bryan D. Cox Ethel C. Garnier-Amblard Tamara R. McBrayer Steven J. Coats Raymond F. Schinazi Franck Amblard 《Bioorganic & medicinal chemistry letters》2017,27(23):5296-5299
Several β-d-2′-deoxy-2′-substituted nucleoside analogs have displayed potent and selective anti-HCV activities and some of them have reached human clinical trials. In that regard, we report herein the synthesis of a series of 2′-deoxy,2′-dibromo substituted U, C, G and A nucleosides 10a–d and their corresponding phosphoramidate prodrugs 13a–d. The synthesized nucleosides 10a–d and prodrugs 13a–d were evaluated for their inhibitory activity against HCV as well as cellular toxicity. The results showed that the most potent compound was prodrug 13a, which exhibited micromolar inhibitory activity (EC50?=?1.5?±?0.8?µM) with no observed toxicity. In addition, molecular modeling and free energy perturbation calculations for the 5′-triphosphate formed from 13a and related 2′-modified nucleotides are discussed. 相似文献
14.
Yogesh S. Sanghvi Naeem B. Hanna Steven B. Larson Roland K. Robins Ganapathi R. Revankar 《Nucleosides, nucleotides & nucleic acids》2013,32(4):761-774
Abstract A synthesis of 1-(2,3-dideoxy-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (2′,3′-dideoxyribavirin, ddR) is described. Glycosylation of the sodium salt of 1,2,4-triazole-3-carbonitrile (5) with 1-chloro-2-deoxy-3,5-di-0-p-toluoyl-α-D-erythro-pentofuranose (1) gave exclusively the corresponding N-1 glycosyl derivative with β-anomeric configuration (6), which on ammonolysis provided a convenient synthesis of 2′-deoxyribavirin (7). Similar glycosylation of the sodium salt of methyl 1,2,4-triazole-3-carboxylate (2) with 1 gave a mixture of corresponding N-1 and N-2 glycosyl derivatives (3) and (4), respectively. Ammonolysis of 3 furnished yet another route to 7. A four-step deoxygenation procedure using imidazolylthiocarbonylation of the 3′-hydroxy group of 5′-0-toluoyl derivative (9a) gave ddR (11). The structure of 11 was proven by single crystal X-ray studies. In a preliminary in vitro study ddR was found to be inactive against HIV retrovirus. 相似文献
15.
K. V. Antonov I. D. Konstantinova A. I. Miroshnikov 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):153-159
Abstract A new approach to the synthesis of 2′,3′-dideoxyadenosine and 2′,3′-dideoxyinosine based on deoxygenation of 2′,3′-di-O-mesylnucleosides was developed. 相似文献
16.
Shinya KIKUCHI Tomohiro MAEKAWA Katsumaro MINAMOTO Keizo TANIGAWA 《Nucleosides, nucleotides & nucleic acids》2013,32(8):1365-1372
Abstract 2′,3′-Dibromo-2′,3′-dideoxy-5′-O-trityl-2′,3′-secouridine (8) with sdKF gave the 3′,4′-didehydro-2,2′-anhydro nucleoside 9, which was deprotected to 10. Hydrolysis of 9 gave 3′,4′-didehydro-3′-deoxy-5′-O-trityl-2′,3′-secouridine (11a). Similarly, compound 9 with pyridinium halides gave the corresponding 2′-deoxy-2′-halo nucleosides (11b-d). Compound 11d with azide ion gave 2′-azido analogue 11e. Compound 9 with an excess amount of azide ion gave the 2′-azido triazole (13). 相似文献
17.
Panagiotis Ioannidis Björn Classon Bertil Samuelssony Ingemar Kvarnström 《Nucleosides, nucleotides & nucleic acids》2013,32(8):865-877
Abstract 1-(2,3-Dideoxy-3-C-hydroxmethyl-β-D-threo-pentofuranosyl) -,1- (2,3-didehydro-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl) -and 1-(3-C-azidomethyl-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl)uracil, thymine and cytosine were synthesized and evaluated for anti-HIV activity. The synthetic strategy was based on an allylic alcohol transposition of the corresponding 3′-C-methylene-nucleoside analogues. 相似文献
18.
Naina A. Van Draanen George W. Koszalka 《Nucleosides, nucleotides & nucleic acids》2013,32(8):1679-1693
Abstract A series of α-L-2′,3′-dideoxy nucleosides was prepared as potential antiviral agents. The pyrimidine nucleosides were prepared by standard Vorbrüggen coupling reactions. The purine analogues were prepared by enzymatic transfer of the dideoxy sugar from a pyrimidine to a purine base. These compounds were inactive against HIV-1, HBV, HSV-1 and -2, VZV, and HCMV. 相似文献
19.
Naveen C. Srivastav Neeraj Shakya Michelle Mak Chao Liang D. Lorne J. Tyrrell Babita Agrawal Rakesh Kumar 《Bioorganic & medicinal chemistry》2010,18(21):7542-7547
Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) lead to serious liver diseases worldwide. Co-infection with HBV and HCV is very common and is associated with increased risk of liver pathogenesis, liver cancer, and liver failure. Several 5-substituted 3′-fluoro (or chloro) (1–4, 6, 7, 17–19) and 2′,3′-difluoro 2′,3′-dideoxynucleosides (15 and 16) were synthesized and evaluated for in vitro antiviral activities against duck hepatitis B virus (DHBV), human hepatitis B virus, and hepatitis C virus. Of these compounds 4, 7, 17, and 19 demonstrated moderate anti-HBV activity, and 2, 4, 7, 8, and 19 were weak inhibitors of HCV. Although 5-iodo derivative (7) was most inhibitory against HCV, it exhibited a reduction in cellular RNA levels in Huh-7 cells. The 5-hydroxymethyl-3′-fluoro-2′,3′-dideoxyuridine (4) and 1-(3-chloro-2,3-dideoxy-β-d-erythro-pentofuranosyl)-5-fluorouracil (19) provided the most inhibition of both viruses without cytotoxicity. 相似文献
20.
Biserka Kasnar Dean S. Wise Louis S. Kucera John C. Drach Leroy B. Townsend 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):459-479
Abstract The synthesis of 4-methoxy-, 4-amino-3-chloro-, and 4-amino-1-(2,3-dideoxy-B-D-glycero-pentofuranosyl)pyridazin-6-one nucleosides, 6,19 and 20 is described. The synthesis of 3,4-dichloropyridazin-6-one (10) was accomplished in 44% overall yield using bromomaleic anhydride (17) as the starting material. The condensation of the silylated base of 10 with the halogenose 12 in the presence of trimethylsilyl triflate as a catalyst afforded a mixture of3,4-dichloro-1-(3,5-di-O-p-toluoyl-2-deoxy-B-D-erythro-pentofuranosyl)pyrridazin-6-one (13) in 67% and its α-anomer 14 in 12% yield, respectively. A series of 3′-sulfonate esters were prepared to explore the synthesis of 3-chloro-4-hydroxy-1-(3-azido-2,3-dideoxy-B-D-erythro-pentofuranosyl) pyridazin-6-one (32) via 6,3-anhydronucleoside analogues. Compounds 15, 19 and 20 were evaluated against human immunodeficiency virus, human cytomegalovirus, and herpes simplex virus type 1 but were inactive. 相似文献