- Synthesis of 5'-ethynyl-2'-deoxynucleoside analogues as building block for antisense oligonucleotide
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New nucleosides and nucleoside analogue dimers were prepared using 5'- ethynyl-2'-deoxynucleoside as starting material.
- Lazrek, Hassan B.,Rochdi, Abdelalli,Engels, Joachim W.
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Read Online
- Synthesis and antiviral activity of boranophosphonate isosteres of AZT and d4T monophosphates
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We report synthesis, in vitro antiviral activity, and stability studies in biological media of original boranophosphonate isosteres of AZT and d4T monophophates. A convenient route for the synthesis of 3′-Azido-3′-deoxythymidine-5′-boranophosphonate 8 and 2′,3′-Didehydro-3′-dideoxythymidine-5′-boranopho sphonate 12 is described. H-phosphinates 7 and 11, and α-boranophosphonates 8 and 12 exhibited no significant in vitro activity against HIV-infected cells, neither against a broad panel of viruses, up to 200 μM. The absence of activity of target compounds 8 and 12 can be partially explained by their short half-life in culture medium.
- Barral, Karine,Priet, Stéphane,De Michelis, Céline,Sire, Joséphine,Neyts, Johan,Balzarini, Jan,Canard, Bruno,Alvarez, Karine
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- Deoxynucleic Guanidines (DNG)- Modified Oligonucleotides and Methods of Synthesizing Deoxynucleic Guanidine Strands
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Disclosed herein are spherical nucleic acids (SNAs) comprising oligonucleotides comprising one or more modified oligonucleotides, and methods of use thereof. Also disclosed are methods of synthesizing modified oligonucleotides for use in therapeutics, inc
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Paragraph 0104; 0106
(2021/01/22)
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- Mercury-Free Automated Synthesis of Guanidinium Backbone Oligonucleotides
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A new method for synthesizing deoxynucleic guanidine (DNG) oligonucleotides that uses iodine as a mild and inexpensive coupling reagent is reported. This method eliminates the need for the toxic mercury salts and pungent thiophenol historically used in me
- Skakuj, Kacper,Bujold, Katherine E.,Mirkin, Chad A.
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supporting information
p. 20171 - 20176
(2020/01/02)
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- Mitochondrial mode of action of a thymidine-based cisplatin analogue breaks resistance in cancer cells
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Cisplatin analogue complexes with platinum(II) and palladium(II) starting from 3′,5′-diamino-3′,5′-dideoxy-thymidines were synthesized, both with the D-erythro- and D-threo configurations. Complexes of the general formula [MCl2L] were obtained and characterized. NMR spectroscopic measurements and single crystal X-ray structure analysis showed that the metal centers are coordinated to the ligands by the amino groups in 3′- and 5′-positions and not through the thymine moiety. All ligands and complexes showed no significant in vitro activities except thymiplatin (cis-dichloro(3′,5′-diamino-3′,5′-dideoxy-D-threo- thymidine)platinum(II)). Detailed in vitro studies on the apoptosis pathway in lymphoma (BJAB), leukemia (NALM-6), and melanoma cells (Mel-HO) as well as on transfected or resistant cell lines were carried out. Thymiplatin significantly induced an apoptotic response, which was found to be associated with the loss of mitochondrial membrane potential and with caspase activation. The activity was shown to be independent of Fas-associated protein with death domain (FADD), but dependent on Bcl-2 expression. As a consequence, for thymiplatin a mitochondrial mode of action could be assigned. Moreover, the compound showed activity in cells resistant to common drugs, such as daunorubicin and vincristin, and showed synergistic effects with doxorubicin, vincristin, cytarabin, and daunorubicin. Prove your metal: Cisplatin analogues with platinum(II) and palladium(II) complexes based on 3′,5′-diamino thymidines were synthesized (see figure for an example) and one was found to induce apoptosis mediated by caspase-9 and -3 processing. Thymiplatin was proven to be active on cisplatin, vincristin and daunorubicin resistant leukemia cells, and was synergistic with cytarabin, vincristin, daunorubicin, and doxorubicin in lymphoma cells. Copyright
- Onambele, Liliane A.,Koth, Daniel,Czaplewska, Justyna A.,Schubert, Ulrich S.,Goerls, Helmar,Yano, Shigenobu,Obata, Makoto,Gottschaldt, Michael,Prokop, Aram
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supporting information; experimental part
p. 14498 - 14505
(2011/03/21)
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- The synthesis and NMR investigation on novel boron derivatives of stavudine
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Preparation and spectroscopic properties of novel boron-containing derivatives of anti-HIV agent stavudine are presented, The new compounds, (5′-O-(4,4,5,5-tetramethyl-1,3,2-dioxaboronate)-2′-3′-didehydro-2′-3′-dideoxythymidine and 5′-O-(dihydroxyboronate)-2′-3′-didehydro-2′-3′-dideoxythymidine), were prepared by direct reaction between stavudine and reagents containing B{single bond}H moieties - pinacolborane and borane-dimethylsulfide complexes, respectively. The boron coordination equilibrium of those compounds was analyzed by water titration monitored by NMR. Results of the DFT calculations and NMR experiments pointed to structural and electronic similarity of tetrahedral boron complexes to phosphate group.
- Ruman, Tomasz,Dlugopolska, Karolina,Jurkiewicz, Agata,Rydel, Katarzyna,Les, Andrzej,Rode, Wojciech
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experimental part
p. 87 - 91
(2010/07/02)
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- Synthesis and anti-HIV-1 activities of novel podophyllotoxin derivatives
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In order to explore the range of biological activities of the podophyllotoxin compound class, a novel series of derivatives of podophyllotoxin, which were conjugates containing stavudine and different structural podophyllotoxin analogues, were designed, synthesized, and evaluated for their anti-HIV-1 activities in vitro. Among these compounds, 19d and 19c showed the highest anti-HIV-1 activities with EC50 values of 0.17 and 0.29 μM and TI values of 466.9 and 354.5, respectively.
- Chen, Shi-Wu,Wang, Yun-Hua,Jin, Yan,Tian, Xuan,Zheng, Yong-Tang,Luo, Du-Qiang,Tu, Yong-Qiang
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p. 2091 - 2095
(2008/02/02)
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- Deoxynucleic guanidine: Synthesis and incorporation of purine nucleosides into positively charged DNG oligonucleotides
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The synthesis of purine nucleosides capable of making the guanidinium linkage is described for the first time starting from the corresponding 2′-deoxynucleosides. The positively charged mixed base DNG oligomer containing guanine was synthesized on solid-p
- Challa, Hemavathi,Bruice, Thomas C.
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p. 1475 - 1481
(2007/10/03)
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- Simple and efficient method for the synthesis of 2′,3′-didehydro-3′-deoxythymidine (d4T)
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2′,3′-Didehydro-3′-deoxythymidine (d4T) is an orally active antiviral drug used in the treatment of AIDS. A novel two-step synthetic method was developed for the synthesis of d4T using inexpensive reagents. An improvement in the yield was achieved for the conversion of the intermediate oxetane to d4T. This is the first simple and efficient method for the large-scale synthesis of d4T.
- Paramashivappa,Phani Kumar,Subba Rao,Srinivasa Rao
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p. 1003 - 1005
(2007/10/03)
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- Synthesis of new homo and heterodinucleosides containing the 2′,3′-dideoxynucleosides AZT and D4T
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The synthesis of new dinucleosides of AZT and D4T is described.
- Taourirte,Lazrek,Vasseur,Ferrero,Fernandez,Gotor
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p. 959 - 962
(2007/10/03)
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- Synthesis of 5'-thioalkyl, sulfoxide and sulfone pyrimidine nucleosides
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The preparation of 5'-thioalkyl, sulfoxide and sulfone pyrimidine nucleosides is [4-11] is described. The key steps of this synthesis are the nucleophilic displacements of a chlorine by a thioalkyl sodium salt or the direct introduction of the thioalkyl group under Mitsunobu conditions.
- Agrofoglio,Girard,Fleury,Leonce
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p. 599 - 600
(2007/10/03)
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- Synthesis of 3′,5′-dithiothymidine and related compounds
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When 3′,5′-di-O-mesylthymidine 7 is heated first with Methylamine in ethanol solution and then with the sodium salt of 4-methoxyphenylmethanethiol 9 in N,N-dimethylacetamide (DMA) solution, the bis(sulfide) 11a is obtained in high yield; when the dimesyl
- Eleuteri, Alessandra,Reese, Colin B.,Song, Quanlai
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p. 2237 - 2240
(2007/10/03)
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- Process for large-scale preparation of 2',3'-didehydro-2',3'-dideoxynucleosides
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An improved process suitable for large-scale production of 2',3'-didehydro-3'-deoxythymidine (d4T) and close analogs is disclosed. The improved process yields d4T in high yield and purity without the use of hazardous reactions or reagents and incorporates several process improvements important on a large scale including a novel purification step involving the isolation of a d4T.N-methylpyrrolidinone solvate.
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- Synthesis of Some 2',3'-Didehydro-2',3'-didepxynucleosodes Derived from Modified Pyrimidine Bases
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3',5'-Bis-O-(4-tolylsulfonyl)-thymidine and 2'-deoxyuridine (13a and 13b) reacted with sodium ethoxide in boiling ethanol to give the corresponding ethoxy-oxetanes 12a and 12b in 67 and 66percent overal yield for the two-step processes starting from thymidine 4a and 2'-deoxyuridine 4b, respectively.Treatment of the ethoxy-oxetanes 12a and 12b with hydrogen sulfide and N1,N1,N3,N3-tetramethylguanidine in dry pyridine solution gave the 2-thiothymine- and 2-thiouracyl-derived oxetanes 19a and 19b in 62 and 68.5percent yield, respectively.When the latter compounds were treated with potassium tert-butoxide in dimethyl sulfoxide, the corresponding 2',3'-didehydro-2',3'-dideoxynucleosides (d4 nucleosides) 10a and 10b were obtained in 66 and 60percent yield, respectively.The 2-thiothymine-derived oxetane 19a was converted via the 5-methyl-2-thiocytosine-derived oxetane 21a into the 5-methyl-2-thiocytosine-derived d4 nucleoside 11a in 59.5percent overall yield; the 2-thiouracil-derived oxetane 19b was similarly converted into the 2-thiocytosine- and 4-N-methyl-2-thiocytosine-derived d4 nucleosides 11b and 23 in 51 and 50percent overall yield, respectively.Finally, the ethoxy-oxetane 12b was converted into the corresponding amino- and methylamino-oxetanes 25a and 25b in 74 and 83percent yield, respectively.The latter compound, 25b, was succesively converted into the 2-N-methylisocytosine-derived d4 nucleoside 26b in 62percent yield.
- Reese, Colin B.,Varaprasad, Chamakura V. N. S.
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p. 189 - 196
(2007/10/02)
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- Prodrugs of 2',3'-didehydro-3'-deoxythymidine
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Six ester prodrugs of 2',3'-didehydro-3'-deoxythymidine (D4T) were synthesized, and their physicochemical properties were evaluated. Marked differences were observed. All of the prodrugs were chemically stable within the pH range 2-7. Hydrolysis of these esters was observed in all cases for four rat enzyme systems (plasma, liver, duodenum, and kidney), with D4T being regenerated. D4T or the prodrug was administered orally to rats, and the plasma concentrations of D4T and a corresponding prodrug were measured. The half-life of D4T after intravenous administration was 35.9 min. The half- life calculated from the terminal phase and the maximum concentration in plasma following oral administration of D4T were 35.9 min and 48.4 μM, respectively. After oral prodrug administration (with water or olive oil as a solvent), though none of the prodrugs was detected in plasma except for 5'- hemisuccinyl D4T and 5'-hemiglutaryl D4T with olive oil as a solvent, retention time of plasma D4T concentration was extended and the elevated D4T concentration in plasma decreased.
- Hasegawa,Seki,Juni,Saneyoshi,Kawaguchi
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p. 1232 - 1236
(2007/10/02)
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- Conversion of Some Pyrimidine 2'-Deoxyribonucleosides into the Corresponding 2',3'-Didehydro-2',3'-dideoxynucleosides
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Thymidine 4b was converted into 2,3'-anhydro-1-(2'-deoxy-β-D-threo-pentofuranosyl)thymine 7b in ca. 65percent isolated yield by being heated at 155 deg C with an excess of diphenyl sulfite and 1-methylimidazole in N,N-dimethylacetamide solution. 2'-Deoxyuridine 4a, 2'-deoxy-5-ethyluridine 4c and 2'-deoxy-5-fluorouridine 4d were similarly converted into 2,3'-anhydronucleosides which were isolated as their 5'-O-(tert-butyldimethylsilyl) derivatives 8a, 8c and 8d in 51, 50 and 59percent yield, respectively.When the oxetane derivatives 5a-d, prepared by the literature procedure from the parent 2'-deoxynucleosides 4a-d, were heated with an excess of sodium hydride in N,N-dimethylacetamide solution at 100 deg C, they were converted into the corresponding 2',3'-didehydro-2',3'-dideoxynucleosides 6a-d in 68, 76, 69 and 74percent isolated yield, respectively.The latter compounds were similarly prepared from the 2,3'-anhydronucleosides 7a-d in 71, 81, 69 and 74percent isolated yield, respectively. 2,3'-Anhydro-5'-O-(tert-butyldimethylsilyl)-2'-deoxy-5-(trifluoromethyl)- and -5-iodo-1-(β-D-threo-pentofuranosyl)uracil 8e and 8f, which were themselves prepared from the parent 2'-deoxynucleosides 4e and 4f, respectively, in ca. 60 and 50percent yield, were converted by a three-step procedure via the intermediate 2'-deoxy-3'-(phenylseleno) derivatives 10e and 10f into the corresponding 2',3'-didehydro-2',3'-dideoxynucleosides 6e and 6f in 52 and 49percent overall yield, respectively.Compound 8e was also converted into 2',3'-dideoxy-5-(trifluoromethyl)uridine 11b and 3'-azido-2',3'-dideoxy-5-(trifluoromethyl)uridine 11c in 49 and 66percent overall yield, respectively.
- Joshi, Bhalchandra V.,Rao, T. Sudhakar,Reese, Colin B.
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p. 2537 - 2544
(2007/10/02)
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- Fluorinated sugar analogues of potential anti-HIV-1 nucleosides
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In order to obtain agents with therapeutic indices superior to those of AZT, FLT, or D4T, several analogues of anti-HIV-1 nucleosides were synthesized. These include 2',3'-dideoxy-2',3'-difluoro-5-methyluridine (13), its arabino analogue 19, arabino-5-met
- Huang,Chen,Wang,Kim,Warshaw,Armstrong,Zhu,Chou,Watanabe,Matulic-Adamic,Su,Fox,Polsky,Baron,Gold,Hardy,Zuckerman
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p. 1640 - 1646
(2007/10/02)
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- Production of 2',3'-dideoxy-2',3'-didehydronucleosides
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There are disclosed novel processes for producing 2',3'-dideoxy-2'3'-didehydronucleosides, for example, 2',3'-dideoxy-2',3'-didehydrothymidine in high yields and on a large scale. The compounds so-produced are useful as antiviral agents, especially as agents effective against the human immunodeficiency viruses (HIV).
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- 1 (2,3 Dideoxy β-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent
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The nucleoside analogue 1 (2,3 dideoxy-β-D-glycero-pent-2-enofuranosyl)thymine (d4T, 1) was prepared by ring opening of the 3',5'-anhydro compound 5. This method has been refined such that it can be used to prepare d4T (1) on a large scale. The triphosphate of d4T (8) was also synthesized from 1 in order to examine the mode of action. The in vitro inhibitory activity of d4T was found to be comparable to that of AZT in HIV-infected CEM cells. The triphosphate of d4T (8) and that of AZT inhibited the HIV reverse transcriptase with poly(rA):oligo(dT) as the template:primer with K(i) values of 0.032 and 0.007 μM, respectively. The in vitro toxicity of d4T against normal human hematopoietic progenitor cells (CFU-GM) was measured in comparison to AZT. While d4T reduces colony-forming units by 50% at a concentration of 100 μM, it takes only 1 μM AZT to have a similar toxic effect. With erythrocyte burst forming units (BFU-E) the in vitro toxicities for d4T and AZT have comparable ID50 values of 10 and 6.7 μM, respectively.
- Mansuri,Starrett Jr.,Ghazzouli,Hitchcock,Sterzycki,Brankovan,Lin,August,Prusoff,Sommadossi,Martin
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p. 461 - 466
(2007/10/02)
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