Synlett 2024; 35(06): 716-720
DOI: 10.1055/s-0042-1751508
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Special Issue to Celebrate the Centenary Year of Prof. Har Gobind Khorana

Synthesis and Properties of 2′-Deoxyadenosine Mimics Bearing a Thieno[3,2-d]pyrimidine Ring

Yasufumi Fuchi
,
Miho Kawaguchi
,
Yuta Ito
,
Yoshiyuki Hari  ∗
This work was supported by a Grant-in-Aid for Early-Career Scientists (Grant Number 20K15963 for Y.F.) from the Japan Society for Promotion Sciences (JSPS).
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Abstract

A C-nucleoside with a stable C–C glycosidic bond can be used as a building block for chemically modified oligonucleotides (ONs). In this study, two adenosine-like C-nucleosides (dSA and dSO2A) bearing thieno[3,2-d]pyrimidine rings were designed and synthesized. These analogues were synthesized via the Heck reaction, and their properties as monomer nucleosides were investigated. Both the dSA and dSO2A monomers were not recognized by adenosine deaminase (ADA). In addition, they exhibited fluorescence emissions in the UV and visible regions of dSA and dSO2A, respectively. Subsequently, dSA was converted into a phosphoramidite compound and incorporated into the ONs. The synthesized dSA-modified ONs formed a stable duplex with DNA and RNA complements comparable to natural adenosine. Furthermore, the modified ONs exhibited fluorescence emission derived from dSA.

Key words

C-nucleoside - adenosine mimic - thienopyrimidine - oligonucleotide - fluorescence

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0042-1751508.
  • Supporting Information


Publication History

Received: 24 July 2023

Accepted after revision: 12 September 2023

Article published online:
18 October 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • References and Notes

  • 1 Zhang M, Kong L, Gong R, Iorio M, Donadio S, Deng Z, Sosio M, Chen W. Microb. Cell Fact. 2022; 21: 1
    CrossrefPubMed
    • 3a Nishimura H, Mayama M, Komatsu Y, Kato H, Shimaoka N, Tanaka Y. J Antibiot. 1964; 17: 148
    • 3b Nakagawa Y, Kano H, Tsukuda Y, Koyama H. Tetrahedron Lett. 1967; 8: 4105
      CrossrefPubMed
    • 4a Koyama G, Maeda K, Umezawa H, Iitaka Y. Tetrahedron Lett. 1966; 7: 597
      CrossrefPubMed
    • 4b Robins RK, Townsend LB, Cassidy F, Gerster JF, Lewis AF, Miller RL. J. Heterocycl. Chem. 1966; 3: 110
      Crossref
    • 4c Wang SA, Ko Y, Zeng J, Geng Y, Ren D, Ogasawara Y, Irani S, Zhang Y, Liu HW. J. Am. Chem. Soc. 2019; 141: 6127
      CrossrefPubMed
    • 5a Morais P, Adachi H, Yu YT. Front. Cell Dev. Biol. 2021; 9: 1
      CrossrefPubMed
    • 5b Karikó K, Muramatsu H, Welsh FA, Ludwig J, Kato H, Akira S, Weissman D. Mol. Ther. 2008; 16: 1833
      CrossrefPubMed
    • 6a Bzowska A, Kulikowska E, Shugar D. Biochim. Biophys. Acta, Protein Struct. Mol. Enzymol. 1992; 1120: 239
      CrossrefPubMed
    • 6b Long MC, Parker WB. Biochem. Pharmacol. 2006; 71: 1671
      CrossrefPubMed
    • 6c Wierzchowski J, Antosiewicz JM, Shugar D. Mol. Biosyst. 2014; 10: 2756
      CrossrefPubMed
    • 7a Ward DC, Reich E. Proc. Natl. Acad. Sci. U.S.A. 1968; 61: 1494
      CrossrefPubMed
    • 7b Ward DC, Cerami A, Reich E, Acs G, Altwerger L. J. Biol. Chem. 1969; 244: 3243
      CrossrefPubMed
    • 8a De Clercq E. J. Med. Chem. 2016; 59: 2301
      CrossrefPubMed
    • 8b Eastman RT, Roth JS, Brimacombe KR, Simeonov A, Shen M, Patnaik S, Hall MD. ACS Cent. Sci. 2020; 6: 672
      CrossrefPubMed
    • 8c Cho A, Zhang L, Xu J, Babusis D, Butler T, Lee R, Saunders OL, Wang T, Parrish J, Perry J, Feng JY, Ray AS, Kim CU. Bioorg. Med. Chem. Lett. 2012; 22: 4127
      CrossrefPubMed
    • 9a Shin D, Sinkeldam RW, Tor Y. J. Am. Chem. Soc. 2011; 133: 14912
      CrossrefPubMed
    • 9b Rovira AR, Fin A, Tor Y. J. Am. Chem. Soc. 2015; 137: 14602
      CrossrefPubMed
    • 9c Rovira AR, Fin A, Tor Y. Chem. Sci. 2017; 8: 2983
      CrossrefPubMed
    • 10a Park S, Otomo H, Zheng L, Sugiyama H. Chem. Commun. 2014; 50: 1573
      CrossrefPubMed
    • 10b Lefoix M, Mathis G, Kleinmann T, Truffert J.-C, Asseline U. J. Org. Chem. 2014; 79: 3221
      CrossrefPubMed
  • 11 Shao X, Abdelkhalek A, Abutaleb NS, Velagapudi UK, Yoganathan S, Seleem MN, Talele TT. J. Med. Chem. 2019; 62: 9772
    CrossrefPubMed
  • 12 Temburnikar KW, Zimmermann SC, Kim NT, Ross CR, Gelbmann C, Salomon CE, Wilson GM, Balzarini J, Seley-Radtke KL. Bioorg. Med. Chem. 2014; 22: 2113
    CrossrefPubMed
  • 13 Kemnitzer W, Sirisoma N, May C, Tseng B, Drewe J, Cai SX. Bioorg. Med. Chem. Lett. 2009; 19: 3536
    CrossrefPubMed
  • 14 Tor Y, Del Valle S, Jaramillo D, Srivatsan SG, Rios A, Weizman H. Tetrahedron 2007; 63: 3608
    CrossrefPubMed
    • 15a Wellington KW, Benner SA. Nucleosides, Nucleotides Nucleic Acids 2006; 25: 1309
      CrossrefPubMed
    • 15b Stambaský J, Hocek M, Kočovský P. Chem. Rev. 2009; 109: 6729
      CrossrefPubMed
  • 16 Hegelein A, Müller D, Größl S, Göbel M, Hengesbach M, Schwalbe H. Chem. Eur. J. 2020; 26: 1800
    CrossrefPubMed
  • 17 Synthesis of dSA To a solution of compound 5 (38 mg, 70 μmol) in CH2Cl2 (1 mL), TFA (0.2 mL) was added at room temperature under an argon atmosphere. The reaction mixture was stirred for 17 h followed by addition of MeOH. The resulting mixture was concentrated in vacuo. Subsequently, CHCl3 was added to the residue, and the resulting precipitate was collected by filtration. The collected solid was dried in vacuo to obtain compound dSA (15 mg, 81%) as a white solid. IR (ATR): 3329, 3200, 2924, 1643, 1579, 1513 cm–1. 1H NMR (500 MHz, CD3OD): δ = 8.33 (1 H, s), 7.98 (1 H, s), 5.49 (1 H, dd, J = 11.0, 5.5 Hz), 4.46 (1 H, d, J = 5.5 Hz), 4.06–4.05 (1 H, m), 3.81 (1 H, dd, J = 12.0, 3.0 Hz), 3.71 (1 H, dd, J = 12.0, 3.0 Hz), 2.42 (1 H, ddd, J = 13.0, 11.0, 5.5 Hz), 2.22 (1 H, dd, J = 13.0, 5.5 Hz). 13C NMR (125 MHz, CD3OD): δ = 160.4, 157.7, 154.8, 138.1, 131.4, 117.4, 89.7, 77.9, 75.2, 64.5, 58.3, 49.8, 43.0, 18.4. HRMS (ESI-TOF): m/z [M – H]– calcd for C11H12N3O3S: 266.0599; found: 266.0599.
  • 18 Synthesis of dSO2A To a solution of compound 9 (289 mg, 0.5 mmol) in CH2Cl2 (5 mL), TFA (0.25 mL) was added at room temperature under an argon atmosphere. The reaction mixture was stirred for 2 days and then quenched with NaHCO3 and MeOH. The resulting mixture was filtered, and then the filtrate was concentrated in vacuo. Subsequently, a solution of CHCl3/MeOH (1:1) was added to the residue, and the resulting precipitate was collected by filtration. The collected solid was dried in vacuo to obtain compound dSO2A (92 mg, 62%) as a gray solid. IR (ATR): 3508, 3376, 3331, 3135, 3084, 1670, 1591, 1537, 1499 cm–1. 1H NMR (500 MHz, DMSO-d 6): δ = 8.58 (1 H, s), 7.95 (2 H, br s), 7.46 (1 H, d, J = 2.0 Hz), 5.15 (1 H, d, J = 5.0 Hz), 5.12 (1 H, ddd, J = 10.0, 6.0, 2.0, Hz), 4.77 (1 H, t, J = 6.0 Hz), 4.19–4.18 (1 H, m), 3.80 (1 H, dt, J = 5.0, 2.0 Hz), 3.45–3.36 (2 H, m), 2.31 (1 H, ddd, J = 13.0, 6.0, 2.0 Hz), 1.79 (1 H, ddd, J = 13.0, 10.0, 5.0 Hz). 13C NMR (125 MHz, DMSO-d 6): δ = 162.2, 158.1, 154.4, 148.1, 129.2, 109.0, 87.6, 72.9, 71.8, 62.0, 40.5. HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H13N3O5NaS: 322.0468; found: 322.0474.
  • 19 Cristalli G, Costanzi S, Lambertucci C, Lupidi G, Vittori S, Volpini R, Camaioni E. Med. Res. Rev. 2001; 21: 105
    CrossrefPubMed
  • 20 An authentic sample of dSI was successfully obtained in 78% yield by the chemical conversion of dSA (see the Supporting Information). In contrast, for the preparation of an authentic sample of dSO2I, the chemical conversion of dSO2A into the corresponding dSO2I could not be achieved because of the low reactivity of the 4-amino group of dSO2A.
  • 21 Sinkeldam RW, McCoy LS, Shin D, Tor Y. Angew. Chem. Int. Ed. 2013; 52: 14026
    CrossrefPubMed
  • 22 Ludford PT, Yang S, Bucardo MS, Tor Y. Chem. Eur. J. 2022; 28: e202104472
    CrossrefPubMed
  • 23 Chen RF. Anal. Lett. 1967; 1: 35
    CrossrefPubMed
  • 24 Heinlein T, Knemeyer JP, Piestert O, Sauer M. J. Phys. Chem. B 2003; 107: 7957
    CrossrefPubMed