Recent Advances in Triazolyl Nucleosides

  • Smriti Srivastava
  • Vipin K. Maikhuri
  • Divya Mathur
  • Ashok K. PrasadEmail author
Conference paper


Nucleosides and its modified analogues are important components and possess key roles in various biological processes. Copper catalyzed 1,3-dipolar cycloadditions have been emerged as an excellent tool to join azide and alkyne moieties to form triazolyl compounds. Presence of triazole group enhances the therapeutic potential as well as fluorescence properties of the modified nucleosides. Owing to the designing and development of the new triazolyl nucleosides for their various biological and photophysical application at faster pace, there is a need to have knowledge of the recent developments in this area. The review herein highlights the various modifications, therapeutic importance and other applications of recently reported triazolyl-nucleosides.


  1. 1.
    (a) Matsuda A, Sasaki T (2004) Antitumor activity of sugar-modified cytosine nucleosides. Cancer Sci 95:105; (b) Vester B, Wengel J (2004) LNA (Locked Nucleic Acid): High-Affinity targeting of complementary RNA and DNA. Biochemistry 43:13233; (c) Russ P, Schelling P, Scapozza L, Folkers G, De Clercq E, Marquez VE (2003) Synthesis and biological evaluation of 5-substituted derivatives of the potent antiherpes agent (north)-Methanocarbathymine. J Med Chem 46:5045; (d) Agrofoglio LA, Challand SR, Huryn DM, Okabe M (1992) AIDS driven nucleoside chemistry. Chem Rev 92:1745Google Scholar
  2. 2.
    (a) Aartsma-Rus A (2012) Overview on AON design. Methods Mol Biol 867:117; (b) Yamamoto T, Harada-Shiba M, Nakatani M, Wada S, Yasuhara H, Narukawa K, Sasaki K, Shibata MA, Torigoe H, Yamaoka T, Imanishi T, Obika S (2012) Cholesterol-lowering action of BNA-based Antisense Oligonucleotides targeting PCSK9 in Atherogenic Diet-induced Hypercholesterolemic Mice. Mol Ther Nucleic Acids 1:22; (c) Bennett CF, Swayze EE (2010) RNA targeting therapeutics: molecular mechanisms of antisense Oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 50:259. (d) Kole R, Krainer AR, Altman S (2012) RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov 11:125; (e) Dagle JM, Weeks DL, Walder JA, (1991) Pathways of degradation and mechanism of action of antisense oligonucleotides in Xenopus laevis embryos. Antisense Res Dev 1:11; (f) Eder PS, Devine RJ, Dagle JM, Walder JA (1991) Substrate specificity and kinetics of degradation of antisense oligonucleotides by a 3′ exonuclease in plasma. Antisense Res Dev 1:141Google Scholar
  3. 3.
    Mickelfield J (2001) Backbone modification of nucleic acid: synthesis, structure and therapeutic applications. Curr Med Chem 8:1157Google Scholar
  4. 4.
    Sipa K, Sochacka E, Kazmierczak-Baranska J, Maszewska M, Janicka M, Nowak G, Nawrot B (2007) Effect of base modifications on structure, thermodynamic stability, and gene silencing activity of short interfering RNA. RNA 13:1301Google Scholar
  5. 5.
    Prakash TP (2011) An overview of sugar-modified Oligonucleotides for antisense therapeutics. Chem Biodivers 8:1616Google Scholar
  6. 6.
    Mulamba GB, Hu A, Azad RF, Anderson KP, Coen DM (1998) Human cytomegalovirus mutant with sequence-dependent resistance to the phosphorothioate oligonucleotide fomivirsen (ISIS 2922). Antimicrob Agents Chemother 42:971Google Scholar
  7. 7.
    Merki E, Graham MJ, Mullick AE, Miller ER, Crooke RM, Pitas RE, Witztum JL, Tsimikas S (2008) Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation 118:743Google Scholar
  8. 8.
    Huisgen R (1963) Kinetics and mechanism of 1,3-dipolar cycloadditions. Angew Chem 75:604Google Scholar
  9. 9.
    Meldal M, Tornoe CW (2008) Cu-catalyzed azide-alkyne cycloaddition. Chem Rev 108:2952Google Scholar
  10. 10.
    Kolb HC, Sharpless KB (2003) The growing impact of click chemistry on drug discovery. Drug Discov Today 8:1128; (b) Moses JE, Moorhouse AD (2007) The growing applications of click chemistry. Chem Rev 36:1249Google Scholar
  11. 11.
    (a) Lolk L, Pohlsgaard J, Jepsen AS, Hansen LH, Nielsen H, Steffansen SI, Sparving L, Nielsen AB, Vester B, Nielsen P (2008) A click chemistry approach to pleuromutilin conjugates with nucleosides or acyclic nucleoside derivatives and their binding to the bacterial ribosome. J Med Chem 51:4957 (b) Moustafa AH, Haggam RA, Younes ME, El Ashry ESH (2006) The synthesis of triazolothiadiazines and thiadiazoles from 1,2-bis-(4-amino-5-mercapto-1,2,4-triazol-3-yl)-ethanol and ethane. Phosphorus, Sulfur Silicon Relat Elem 181:2361Google Scholar
  12. 12.
    Moustafa AH, El-Sayed HA, Haikal AEFZ, El Ashry ESH (2011) Synthesis of acyclovir and HBG analogues having Nicotinonitrile and its 2-methyloxy 1,2,3-triazole. Nucleosides Nucleotides Nuclic Acids 30:340Google Scholar
  13. 13.
    (a) El Sadek MM, Abd El-Dayem NS, Hassan SY, Mostafa MA, Yacout GA (2014) Antioxidant and antitumor activities of new synthesized aromatic C-nucleoside derivatives. Molecules 19:5163 (b) Wang M, Xia Y, Fan Y, Rocchi P, Qu F, Iovanna JL, Peng L (2010) A novel arylethynyltriazole acyclonucleoside inhibits proliferation of drug-resistant pancreatic cancer cells. Bioorg Med Chem Lett 20:5979Google Scholar
  14. 14.
     Wu J, Yu W, Fu L, He W, Wang Y, Chai B, Song C, Chang (2013) 2′-deoxy-2′-fluoro-4′-triazole cytidine nucleosides as potent antiviral agents. Eur J Med Chem 63:739Google Scholar
  15. 15.
    Alaoui S, Dufies M, Driowya M, Demange L, Bougrin K, Robert G, Auberger P, Pagès G, Benhida R (2017) Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides. Bioorg Med Chem Lett 27:1989–1992Google Scholar
  16. 16.
    Amdouni H, Robert G, Driowya M, Furstoss N, Métier C, Dubois A, Dufies M, Zerhouni M, Orange F, Gervais SL, Bougrin K, Martin AR, Auberger P, Benhida R (2017) In Vitro and in Vivo evaluation of fully substituted (5-(3-ethoxy-3-oxopropynyl)-4-(ethoxycarbonyl)-1,2,3-triazolyl-glycosides as original nucleoside analogues to circumvent resistance in myeloid malignancies. J Med Chem 60:1523–1533Google Scholar
  17. 17.
    Bodnár B, Mernyák E, Wölfling J, Schneider G, Herman BE, Szécsi M, Sinka I, Zupkó I, Kupihár Z, Kovács L (2016) Synthesis and biological evaluation of triazolyl 13α-estrone–nucleoside. Molecules 21:1212Google Scholar
  18. 18.
    Giofrè SV, Romeo R, Carnovale C, Mancuso R, Cirmi S, Navarra M, Garozzo A, Chiacchio MA (2015) Synthesis and biological properties of 5-(1H-1,2,3-Triazol-4-yl) isoxazolidines: a new class of C-nucleosides. Molecules 20Google Scholar
  19. 19.
    Romeo R, Carnovale C, Giofrè SV, Chiacchio MA, Garozzo A, Amata E, Romeo G, Chiacchio U (2015) C-5′-triazolyl-2′-oxa-3′-aza-4′a-carbanucleosides: synthesis and biological evaluation. Beilstein J Org Chem 11:328–334Google Scholar
  20. 20.
    Zhang Q, He P, Zhou G, Gu Y, Fu T, Xue D, Liu HM (2013) Synthesis and biological evaluation of 2,6-dichloropurine bicyclonucleosides containing a triazolyl-carbohydrate moiety. Carbohyd Res 382:65–70Google Scholar
  21. 21.
    Lakshman MK, Kumar A, Balachandran R, Day BW, Andrei G, Snoeck R, Balzari J (2012) Synthesis and biological properties of C-2 triazolylinosine derivatives. J Org Chem 77:5870–5883Google Scholar
  22. 22.
    Ouahrouch A, Taourirte M, Schols D, Snoeck R, Andrei G, Engels JW, Lazrek HB (2016) Design, synthesis, and antiviral activity of novel ribonucleosides of 1,2,3-triazolylbenzyl-aminophosphonates. Arch Pharm Chem Life Sci 349:30–41Google Scholar
  23. 23.
    Rashad AE, Shamroukh AH, El-Sayed AH, Micky JA, Marsok NA, Abdel-Megeid FME (2016) Some 1,2,4-triazole derivatives: synthesis and antiviral evaluation. Der Pharma Chemica 8(15):75–81Google Scholar
  24. 24.
    Vernekar, Kumar SV, Li Q, Jeana Z, Geraghty RJ, Zhengqiang W (2014) Synthesis and antiviral evaluation of 4′-(1,2,3-triazol-1-yl)thymidines. Med Chem Comm 5(5):603–608Google Scholar
  25. 25.
    Jamal K, Moha T, Christian G, Ivan K, Joachim EW (2013) Microwave-assisted click chemistry for nucleoside functionalization: useful derivatives for analytical and biological applications. Synthesis 45(3):396–405Google Scholar
  26. 26.
    Elayadi H, Smietana M, Vasseur JJ, Balzarini J, Lazrek HB (2014) Synthesis of 1,2,3-triazolyl nucleoside analogs as potential anti-influenza A (H3N2 Subtype) virus agents. Arch Pharm Chem Life Sci 347:134–141Google Scholar
  27. 27.
    Zhou L, Amer A, Korn M, Burda R, Balzarini J, De Clercq E, Kern ER, Torrence PF (2005) Synthesis and antiviral activities of 1,2,3-triazole functionalized thymidines: 1,3-dipolar cycloaddition for efficient regioselective diversity generation. Antivir Chem Chemother 16:375Google Scholar
  28. 28.
    Montague A, Roy V, Balzarini J, Snoeck R, Andrei G, Agrofoglio LA (2011) Synthesis of new C5-(1-substituted-1,2,3-triazol-4 or 5-yl)-2′-deoxyuridines and their antiviral evaluation. Eur J Med Chem 46:778Google Scholar
  29. 29.
    Vernekar SKV, Qiu L, Zacharias J, Geraghty RJ, Wang Z (2014) Synthesis and antiviral evaluation of 4′-(1,2,3-triazol-1-yl)thymidines. Med Chem Commun 5:603Google Scholar
  30. 30.
    Olomola TO, Klein R, Lobb KA, Sayed Y, Kaye PT (2010) Towards the synthesis of coumarin derivatives as potential dual-action HIV-1 protease and reverse transcriptase inhibitors. Tetrahedron Lett 51:6325Google Scholar
  31. 31.
    Hwu JR, Lin SY, Tsay SC, De Clercq E, Leyssen P, Ney J (2011) Coumarin-Purine ribofuranoside conjugates as new agents against hepatitis C virus. J Med Chem 54:2114Google Scholar
  32. 32.
    Xavier NM, Lucas SD, Jorda R, Schwarz S, Loesche A, Csuk R, Oliveira MC (2015) Synthesis and evaluation of the biological profile of novel analogues of nucleosides and of potential mimetics of sugar phosphates and nucleotides. Synlett 26(19):2663–2672Google Scholar
  33. 33.
    Mahony GO, Svensson S, Sundgren A, Grotli M (2008) Synthesis of 2′-([1,2,3]triazol-1-yl)-2′-deoxyadenosines. Nucleosides Nucleotides Nucleic Acids 27:449CrossRefGoogle Scholar
  34. 34.
    Daligaux P, Pomel S, Leblanc K, Loiseau PM, Cavé C (2016) Simple and efficient synthesis of 5′-aryl-5′-deoxyguanosine analogs by azide-alkyne click reaction and their antileishmanial activities. Mol Divers 20:507–519Google Scholar
  35. 35.
    Reddy PV, Saquib M, Mishra NN, Shuklab PK, Shaw AK (2014) Stereoselective synthesis of tetrahydrofuranyl 1,2,3-triazolyl C-nucleoside analogues by ‘click’ chemistry and investigation of their biological activity. ARKIVOC (iv):170–182Google Scholar
  36. 36.
    Tuberculosis; World Health Organization report 2016.
  37. 37.
    GreenFacts. Scientific facts on drug-resistant Tuberculosis.
  38. 38.
    Poecke SV, Munier-Lehmann MH, Helynck O, Froeyen M, Calenbergh SV (2011) Synthesis and inhibitory activity of thymidine analogues targeting Mycobacterium tuberculosis thymidine monophosphate kinase. Bioorg Med Chem 19:7603Google Scholar
  39. 39.
    Tampure AA, Pawar MG, Srivatsan SG (2013) Fluorescent nucleoside analogs: probes for investigating nucleic acid structure and function. Isr J Chem 53:366–378Google Scholar
  40. 40.
    Passays J, Rubay C, Marcelis L, Benjamin E (2017) Synthesis and photophysical properties of triazolyl irIII nucleosides. Eur J Inorg Chem 623–629Google Scholar
  41. 41.
    Bag SS, Talukdar S, Das SK, Pradhan MK, Mukherjee S (2016) Donor/acceptor chromophores-decorated triazolyl unnatural nucleosides: synthesis, photophysical properties and study of interaction with BSA. Org Biomol Chem 14:5088Google Scholar
  42. 42.
    Bag SS, Das SK, Pradhan MK, Jana S (2016) Hybridization accompanying FRET event in labeled natural nucleoside-unnatural nucleoside containing chimeric DNA duplexes. J Photochem Photobiol, B 162:669–673Google Scholar
  43. 43.
    Ozols K, Cırule D, Novosjolova I, Stepanovs D, Liepinsh E, Bizdena E, Turks M (2016) Development of N6-methyl-2-(1,2,3-triazol-1-yl)-2'-deoxyadenosine as a novel fluorophore and its application in nucleotide synthesis. Tetrahedron Lett 57:1174–1178Google Scholar
  44. 44.
    Kovalovs A, Novosjolova I, Bizdena E, Bizane I, Skardziute L, Kazlauskas K, Jursenas S, Turks M (2013) 1,2,3-triazoles as leaving groups in purine chemistry: a three-step synthesis of N6-substituted-2-triazolyl-adenine nucleosides and photophysical properties thereof. Tetrahedron Lett 54:850–853Google Scholar
  45. 45.
    Ingale SA, Seela F (2014) Nucleoside and oligonucleotide pyrene conjugates with 1,2,3-triazolyl or ethynyl linkers: synthesis, duplex stability, and fluorescence changes generated by the DNA-dye connector. Tetrahedron 70:380–391Google Scholar
  46. 46.
    Kosiova I, Kovackova S, Kois P (2007) Synthesis of coumarin–nucleoside conjugates via huisgen 1,3-dipolar cycloaddition. Tetrahedron 63:312–320Google Scholar
  47. 47.
    Kavoosi S, Rayala R, Walsh B, Barrios M, Gonzalez WG, Miksovska J, Mathivathanan L, Raptis RG, Wnuk SF (2016) Synthesis of 8-(1,2,3-triazol-1-yl)-7-deazapurine nucleosides by azide–alkyne click reactions and direct C-H bond functionalization. Tetrahedron Lett 57:4364–4367Google Scholar
  48. 48.
    Seela F, Sirivolua VR (2008) Pyrrolo-dC oligonucleotides bearing alkynyl side chains with terminal triple bonds: synthesis, base pairing and fluorescent dye conjugates prepared by the azide–alkyne “click” reaction. Org Biomol Chem 6:1674–1687Google Scholar
  49. 49.
    Haque MM, Sun H, Liu S, Wang Y, Peng X (2014) Photo-Switchable DNA interstrand cross-link formation by a coumarin-modified nucleotide. Angew Chem Int Ed 53:7001Google Scholar
  50. 50.
    Lopes AB, Wagner P, Alves Rodrigo, de Souza OM, Germain NL, Uziel J, Bourguignon JJ, Schmitt M, Miranda LSM (2016) Functionalization of 2H-1,2,3-Triazole C-Nucleoside Template via N2 Selective Arylation. J Org Chem 81:4540–4549Google Scholar
  51. 51.
    Carmen S, Michael DS, Simon G, Leandro MSM, Regis G, Angelique F, Florian G, Jacques U, Nadege LG (2017) Synthesis of C-Ribosyl-1,2,3-triazolyl Carboxamides. Synthesis 49(9):1993–2002Google Scholar
  52. 52.
    Bag SS, Talukdar S, Matsumoto K, Kundu R (2013) Triazolyl donor/acceptor chromophore decorated unnatural nucleosides and oligonucleotides with duplex stability comparable to that of a natural adenine/thymine pair. J Org Chem 78:278Google Scholar
  53. 53.
    Novosjolova I, Bizdēna E, Turks M (2015) Synthesis of novel 2- and 6-alkyl/arylthiopurine derivatives. Phosphorus Sulfur Silicon 190:1236–1241Google Scholar
  54. 54.
    Upadhyaya K, Ajay A, Mahar R, Pandey R, Kumar B, Shukla SK, Tripathi RP (2013) A strategy to access fused triazoloquinoline and related nucleoside analogues. Tetrahedron 69:8547–8558Google Scholar
  55. 55.
    Kumar P, Chandak N, Nielsen P, Sharma PK (2012) Sulfonamide bearing oligonucleotides: simple synthesis and efficient RNA recognition. Bioorg Med Chem 20:3843–3849Google Scholar
  56. 56.
    Novosjolova I, Bizdena E, Turks M (2013) Application of 2,6-diazidopurine derivatives in the synthesis of thiopurine nucleosides. Tetrahedron Lett 54:6557–6561Google Scholar
  57. 57.
    Paritala H, Suzuki Y, Carroll KS (2013) Efficient microwave-assisted solid phase coupling of nucleosides, small library generation, and mild conditions for release of nucleoside derivatives. Tetrahedron Lett 54:1869–1872Google Scholar
  58. 58.
    Novosjolova I, Bizdēna E, Belyakov S, Turks M (2013) The Synthesis and X-ray studies of 6-pyrrolidinyl-2-triazolyl purine arabinonucleoside. Mater Sci Appl Chem 28:39–44Google Scholar
  59. 59.
    Hornum M, Djukina A, Sassnau AK, Poul Nielsen P (2016) Synthesis of new C-5-triazolyl-functionalized thymidine analogs and their ability to engage in aromatic stacking in DNA : DNA and DNA : RNA duplexes. Org Biomol Chem 14:4436Google Scholar
  60. 60.
    Rad MNS, Behrouz S, Hoseini SJ, Nasrabadi H, Zare MS (2015)  Copper/Graphene/Clay Nanohybrid: a highly efficient heterogeneous nanocatalyst for the synthesis of novel 1,2,3-triazolyl carboacyclic nucleosides via ‘Click’ Huisgen 1,3-dipolar cycloaddition. Helvetica Chimica Acta 98:1210Google Scholar
  61. 61.
    Elayadi H, Lazrek HB (2015) CuSO4/KI as catalyst for the synthesis of 1,4-disubstituted-1,2,3-triazolo-nucleosides. Nucleosides Nucleotides Nucleic Acids 34:433–441Google Scholar
  62. 62.
    Arya A, Mathur D, Tyagi A, Kumar R, Kumar V, Olsen CE, Saxena RK, Prasad AK (2013) Chemoenzymatic synthesis of 3′-deoxy-3′-(4-substituted-triazol-1-yl)-5-methyluridine. Nucleosides Nucleotides Nucleic Acids 32:646Google Scholar
  63. 63.
    Mathur D, Rana N, Olsen CE, Parmar VS, Prasad AK (2015) Cu(I)-catalyzed efficient synthesis of 2′-triazolo-nucleoside conjugates. J Heterocyclic Chem 52:701Google Scholar
  64. 64.
    Jawalekar AM, Meeuwenoord N, Cremers J (Sjef) GO, Overkleeft HS, Marel GA van der, Rutjes FPJT, Floris L van D (2008) Conjugation of nucleosides and oligonucleotides by [3+2] cycloaddition. J Org Chem 73:287–290Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Smriti Srivastava
    • 1
  • Vipin K. Maikhuri
    • 1
  • Divya Mathur
    • 2
  • Ashok K. Prasad
    • 1
    Email author
  1. 1.Department of ChemistryUniversity of DelhiNew DelhiIndia
  2. 2.Department of ChemistryDaulat Ram College, University of DelhiDelhiIndia

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