Skip to main content
SpringerLink
Log in

Development of Middle-Size Molecules for Alkylation to Higher-Order Structures of Nucleic Acids

  • Chapter
  • First Online:
Middle Molecular Strategy

  • 350 Accesses

Abstract

DNA and RNA can adopt many varieties of stable higher-order structure motifs, such as G-quadruplexes (G4s), mismatch, and bulge, in addition to the canonical duplex DNA. Many of these secondary structures were found to be closely related to the control of the gene expression. Therefore, the higher-order structure of nucleic acids is one of the candidates for therapeutic targets. Due to the therapeutic potentials, efforts for the development of small molecule binders to specifically target the higher-order structures of nucleic acids have been intensely carried out. With the aim to augment the stabilization effect, selective alkylation using small molecules targeting the higher-order structures of nucleic acids have also been pursued. In this review, we describe the development of middle-size molecules for alkylation to higher-order structures of nucleic acids. We have designed molecules for the selective alkylation to the higher-order structures of nucleic acids and these molecules consist of a binding group to target the nucleic acids structure and the alkylating moiety. These synthesized molecules exhibited an efficient reactivity to thymine in the target higher-order structures of the nucleic acids.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. McNeill DR, Whitaker AM, Stark WJ, Illuzzi JL, McKinnon PJ, Freudenthal BD, Wilson DM (2020) Functions of the major abasic endonuclease (APE1) in cell viability and genotoxin resistance. Mutagenesis 35:27–38

    Article  CAS  PubMed  Google Scholar 

  2. Yang ZY, Nejad MI, Varela JG, Price NE, Wang YS, Gates KS (2017) A role for the base excision repair enzyme NEIL3 in replication-dependent repair of interstrand DNA cross-links derived from psoralen and abasic sites. DNA Repair 52:1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kingsland A, Maibaum L (2018) DNA base pair mismatches induce structural changes and alter the free-energy landscape of base flip. J Phys Chem B 122:12251–12259

    Article  CAS  PubMed  Google Scholar 

  4. Halder S, Bhattacharyya D (2013) RNA structure and dynamics: a base pairing perspective. Prog Biophy Mol Bio 113:264–283

    Article  CAS  Google Scholar 

  5. Nam Y, Chen C, Gregory RI, Chou JJ, Sliz P (2011) Molecular basis for interaction of let-7 MicroRNAs with Lin28. Cell 147:1080–1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mayr F, Heinemann U (2013) Mechanisms of Lin28-mediated miRNA and mRNA regulation—a structural and functional perspective. Int J Mol Sci 14:16532–16553

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Sugimoto Y, Vigilante A, Darbo E, Zirra A, Militti C, D’Ambrogio A, Luscombe NM, Ule J (2015) hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1. Nature 519:491–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Varshney D, Spiegel J, Zyner K, Tannahill D, Balasubramanian S (2020) The regulation and functions of DNA and RNA G-quadruplexes. Nature Rev Mol Cell Biol 21:459–474

    Article  CAS  Google Scholar 

  9. Hsu STD, Varnai P, Bugaut A, Reszka AP, Neidle S, Balasubramanian S (2009) A G-Rich sequence within the c-kit oncogene promoter forms a parallel G-Quadruplex having asymmetric G-Tetrad dynamics. J Am Chem Soc 131:13399–13409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Phan AT, Kuryavyi V, Burge S, Neidle S, Patel DJ (2007) Structure of an unprecedented G-quadruplex scaffold in the human c-kit promoter. J Am Chem Soc 129:4386–4392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cogoi S, Xodo LE (2006) G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription. Nucleic Acids Res 34:2536–2549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Siddiqui-Jain A, Grand CL, Bearss DJ, Hurley LH (2002) Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc Natl Acad Sci USA 99:11593–11598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mirkin SM (2007) Expandable DNA repeats and human disease. Nature 447:932–940

    Article  CAS  PubMed  Google Scholar 

  14. Pettersson OJ, Aagaard L, Jensen TG, Damgaard CK (2015) Molecular mechanisms in DM1—a focus on foci. Nucleic Acids Res 43:2433–2441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS (2000) Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy. EMBO J 19:4439–4448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fardaei M, Rogers MT, Thorpe HM, Larkin K, Hamshere MG, Harper PS, Brook JD (2002) Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum Mol Genet 11:805–814

    Article  CAS  PubMed  Google Scholar 

  17. Konieczny P, Stepniak-Konieczna E, Sobczak K (2014) MBNL proteins and their target RNAs, interaction and splicing regulation. Nucleic Acids Res 42:10873–10887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Timchenko L (2020) Correction of RNA-Binding Protein CUGBP1 and GSK3 beta signaling as therapeutic approach for congenital and adult myotonic dystrophy type 1. Int J Mol Sci 21:94–112

    Article  CAS  Google Scholar 

  19. Thornton CA, Wang E, Carrell EM (2017) Myotonic dystrophy: approach to therapy. Curr Opin Genet Dev 44:135–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Konieczny P, Selma-Soriano E, Rapisarda AS, Fernandez-Costa JM, Perez-Alonso M, Artero R (2017) Myotonic dystrophy: candidate small molecule therapeutics. Drug Discov Today 22:1740–1748

    Article  CAS  PubMed  Google Scholar 

  21. Lopez-Morato M, Brook JD, Wojciechowska M (2018) Small molecules which improve pathogenesis of myotonic dystrophy type 1. Front Neurol 9:1664–2295

    Article  Google Scholar 

  22. Velagapudi SP, Gallo SM, Disney MD (2014) Sequence-based design of bioactive small molecules that target precursor microRNAs. Nature Chem Biol 10:291–297

    Article  CAS  Google Scholar 

  23. Rzuczek SG, Colgan LA, Nakai Y, Cameron MD, Furling D, Yasuda R, Disney MD (2017) Precise small-molecule recognition of a toxic CUG RNA repeat expansion. Nature Chem Biol 13:188–193

    Article  CAS  Google Scholar 

  24. Angelbello AJ, Defeo ME, Glinkerman CM, Boger DL, Disney MD (2020) Precise targeted cleavage of a r(CUG) repeat expansion in cells by using a small-molecule-deglycobleomycin conjugate. ACS Chem Biol 15:849–855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Angelbello AJ, Rzuczek SG, McKee KK, Chen JL, Olafson H, Cameron MD, Moss WN, Wang ET, Disney MD (2019) Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model. Proc Natl Acad Sci USA 116:7799–7804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Siboni RB, Nakamori M, Wagner SD, Struck AJ, Coonrod LA, Harriott SA, Cass DM, Tanner MK, Berglund JA (2015) Actinomycin D specifically reduces expanded CUG repeat RNA in myotonic dystrophy models. Cell Reports 13:2386–2394

    Article  CAS  PubMed  Google Scholar 

  27. Coonrod LA, Nakamori M, Wang W, Carrell S, Hilton CL, Bodner MJ, Sibori RB, Docter AG, Haley MM, Thornton CA, Berglund JA (2013) Reducing levels of toxic RNA with small molecules. ACS Chem Biol 8:2528–2537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Siboni RB, Bodner MJ, Khalifa MM, Docter AG, Choi JY, Nakamori M, Haley MM, Berglund JA (2015) Biological efficacy and toxicity of diamidines in myotonic dystrophy type 1 models. J Med Chem 58:5770–5780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jenquin JR, Coonrod LA, Silverglate QA, Pelletier NA, Hale MA, Xia GB, Nakamori M, Berglund JA (2018) Furamidine rescues myotonic dystrophy type I associated mis-splicing through multiple mechanisms. ACS Chem Biol 13:2708–2718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li J, Matsumoto J, Bai LP, Murata A, Dohno C, Nakatani K (2016) A ligand that targets CUG trinucleotide repeats. Chem Eur J 22:14881–14889

    Article  CAS  PubMed  Google Scholar 

  31. Li JX, Nakamori M, Matsumoto J, Murata A, Dohno C, Kiliszek A, Taylor K, Sobczak K, Nakatani K (2018) A dimeric 2,9-diamino-1,10-phenanthroline derivative improves alternative splicing in myotonic dystrophy type 1 cell and mouse models. Chem Eur J 24:18115–18122

    Article  CAS  PubMed  Google Scholar 

  32. Arambula JF, Ramisetty SR, Baranger AM, Zimmerman SC (2009) A simple ligand that selectively targets CUG trinucleotide repeats and inhibits MBNL protein binding. Proc Natl Acad Sci USA 106:16068–16073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wong CH, Nguyen L, Peh J, Luu LM, Sanchez JS, Richardson SL, Tuccinardi T, Tsoi H, Chan WY, Chan HYE, Baranger AM, Hergenrother PJ, Zimmerman SC (2014) Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor. J Am Chem Soc 136:6355–6361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nguyen L, Luu LM, Peng SH, Serrano JF, Chan HYE, Zimmerman SC (2015) Rationally designed small molecules that target both the DNA and RNA causing myotonic dystrophy type 1. J Am Chem Soc 137:14180–14189

    Article  CAS  PubMed  Google Scholar 

  35. Lee J, Bai YG, Chembazhi UV, Peng SH, Yum K, Luu LM, Hagler LD, Serrano JF, Chan HYE, Kalsotra A, Zimmerman SC (2019) Intrinsically cell-penetrating multivalent and multitargeting ligands for myotonic dystrophy type 1. Proc Natl Acad Sci USA 116:8709–8714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Serrano JF, Lee J, Curet LD, Hagler LD, Bonson SE, Schuster EJ, Zimmerman SC (2019) Development of novel macrocyclic small molecules that target CTG trinucleotide repeats. Bioorg Med Chem 27:2978–2984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Onizuka K, Usami A, Yamaoki Y, Kobayashi T, Hazemi ME, Chikuni T, Sato N, Sasaki K, Katahira M, Nagatsugi F (2018) Selective alkylation of T-T mismatched DNA using vinyldiaminotriazine-acridine conjugate. Nucleic Acids Res 46:1059–1068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Holz B, Klimasauskas S, Serva S, Weinhold E (1998) 2-Aminopurine as a fluorescent probe for DNA base flipping by methyltransferases. Nucleic Acids Res 26:1076–1083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nakano S, Uotani Y, Uenishi K, Fujii M, Sugimoto N (2005) DNA base flipping by a base pair-mimic nucleoside. Nucleic Acids Res 33:7111–7119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Onizuka K, Ishida K, Mano E, Nagatsugi F (2019) Alkyne-Alkyne photo-cross-linking on the flipping-out field. Org Lett 21:2833–2837

    Article  CAS  PubMed  Google Scholar 

  41. Burge S, Parkinson GN, Hazel P, Todd AK, Neidle S (2006) Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res 34:5402–5415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dai J, Carver M, Yang D (2008) Polymorphism of human telomeric quadruplex structures. Biochimie 90:1172–1183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. You H, Zeng X, Xu Y, Lim CJ, Efremov AK, Phan AT, Yan J (2014) Dynamics and stability of polymorphic human telomeric G-quadruplex under tension. Nucleic Acids Res 42:8789–8795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dailey MM, Miller MC, Bates PJ, Lane AN, Trent JO (2010) Resolution and characterization of the structural polymorphism of a single quadruplex-forming sequence. Nucleic Acids Res 38:4877–4888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Asamitsu S, Obata S, Yu ZT, Bando T, Sugiyama H (2019) Recent progress of targeted G-quadruplex-preferred ligands toward cancer therapy. Molecules 24:429–458

    Article  PubMed Central  CAS  Google Scholar 

  46. Hänsel-Hertsch R, Antonio MD, Balasubramanian S (2017) DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential. Nature Rev Mol Cell Biol 18:279–284

    Article  CAS  Google Scholar 

  47. Asamitsu S, Bando T, Sugiyama H (2019) Ligand design to acquire specificity to intended G-quadruplex structures. Chem Eur J 25:417–430

    Article  CAS  PubMed  Google Scholar 

  48. Sun ZY, Wang XN, Cheng SQ, Su XX, Ou TM (2019) Developing novel G-quadruplex ligands: from interaction with nucleic acids to interfering with nucleic acid-protein interaction. Molecules 24:396–425

    Article  PubMed Central  CAS  Google Scholar 

  49. Antonio MD, McLuckie KIE, Balasubramanian S (2014) Reprogramming the mechanism of action of chlorambucil by coupling to a G-quadruplex ligand. J Am Chem Soc 136:5860–5863

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Doria F, Nadai M, Folini M, Scalabrin M, Germani L, Sattin G, Mella M, Palumbo M, Zaffaroni N, Fabris D, Freccero M, Richter SN (2013) Targeting loop adenines in G-quadruplex by a selective oxirane. Chem Eur J 19:78–81

    Article  CAS  PubMed  Google Scholar 

  51. Nadai M, Doria F, Antonio MD, Sattin G, Germani L, Percivalle C, Palumbo M, Richter SN, Freccero M (2011) Naphthalene diimide scaffolds with dual reversible and covalent interaction properties towards G-quadruplex. Biochimie 93:1328–1340

    Article  CAS  PubMed  Google Scholar 

  52. Antonio MD, Doria F, Richter SN, Bertipaglia C, Mella M, Sissi C, Palumbo M, Freccero M (2009) Quinone methides tethered to naphthalene diimides as selective G-quadruplex alkylating agents. J Am Chem Soc 131:13132–13141

    Article  PubMed  CAS  Google Scholar 

  53. Nadai M, Doria F, Germani L, Richter SN, Freccero M (2015) A photoreactive G-quadruplex ligand triggered by green light. Chem Eur J 21:2330–2334

    Article  CAS  PubMed  Google Scholar 

  54. Verga D, Hamon F, Poyer F, Bombard S, Teulade-Fichou MP (2014) Photo-cross-linking probes for trapping G-quadruplex DNA. Angew Chem Int Ed 53:994–998

    Article  CAS  Google Scholar 

  55. Sato N, Tsuji G, Sasaki Y, Usami A, Moki T, Onizuka K, Yamada K, Nagatsugi F (2015) A new strategy for site-specific alkylation of DNA using oligonucleotides containing an abasic site and alkylating probes. Chem Commun 51:14885–14888

    Article  CAS  Google Scholar 

  56. Sato N, Takahashi S, Tateishi-Karimata H, Hazemi ME, Chikuni T, Onizuka K, Sugimoto N, Nagatsugi F (2018) Alkylating probes for the G-quadruplex structure and evaluation of the properties of the alkylated G-quadruplex DNA. Org Biomol Chem 16:1436–1441

    Article  CAS  PubMed  Google Scholar 

  57. Nagatsugi F, Kawasaki T, Usui D, Maeda M, Sasaki S (1999) Highly efficient and selective cross-linking to cytidine based on a new strategy for auto-activation within a duplex. J Am Chem Soc 121:6753–6754

    Article  CAS  Google Scholar 

  58. Kawasaki T, Nagatsugi F, Ali MM, Maeda M, Sugiyama K, Hori K, Sasaki S (2005) Hybridization-promoted and cytidine-selective activation for cross-linking with the use of 2-amino-6-vinylpurine derivatives. J Org Chem 70:14–23

    Article  CAS  PubMed  Google Scholar 

  59. Onizuka K, Hazemi ME, Sato N, Tsuji G, Ishikawa S, Ozawa M, Tanno K, Yamada K, Nagatsugi F (2019) Reactive OFF-ON type alkylating agents for higher-ordered structures of nucleic acids. Nucleic Acids Res 47:6578–6589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-Ku, Sendai, Miyagi, 980-8577, Japan

    Fumi Nagatsugi & Kazumitsu Onizuka

Authors
  1. Fumi Nagatsugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazumitsu Onizuka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fumi Nagatsugi .

Editor information

Editors and Affiliations

  1. Graduate School of Science, Osaka University, Toyanaka, Osaka, Japan

    Koichi Fukase

  2. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

    Takayuki Doi

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Nagatsugi, F., Onizuka, K. (2021). Development of Middle-Size Molecules for Alkylation to Higher-Order Structures of Nucleic Acids. In: Fukase, K., Doi, T. (eds) Middle Molecular Strategy. Springer, Singapore. https://doi.org/10.1007/978-981-16-2458-2_3

Download citation

Publish with us

Policies and ethics

Search

Navigation