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Dimeric Calixarenes : A New Family of Major Groove Binders

Hu, Wenbin; Blecking, Caroline; Kralj, Marijeta; Šuman, Lidija; Piantanida, Ivo; Schrader, Thomas
Dimeric Calixarenes : A New Family of Major Groove Binders // Chemistry : a European journal, 18 (2012), 12; 3589-3597 doi:10.1002/chem .201100634 (međunarodna recenzija, članak, znanstveni)

Dimeric Calixarenes : A New Family of Major Groove Binders

Hu, Wenbin ; Blecking, Caroline ; Kralj, Marijeta ; Šuman, Lidija ; Piantanida, Ivo ; Schrader, Thomas

Chemistry : a European journal (0947-6539) 18 (2012), 12; 3589-3597

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Nucleic acid recognition ; DNA – RNA – major/minor groove – calixarene ; hydrogen bonds ; molecular modeling ; circular dichroism spectroscopy ; ethidium bromide – DAPI ; fluorescence titration ; UV-vis melting point ; NMR titration

A new class of potent DNA binding agents is presented and characterized with respect to its recognition mechanism. Dimeric calix[4]arenes with cationic groups at their upper rims and flexible alkyl bridges can be synthesized from triply acyl-protected calix[4]arene tetramines in relatively short sequences (3-5 steps). They attach themselves to double-stranded nucleic acids in a noncovalent fashion, with micro- to nanomolar affinities. Guanidinium headgroups with their extended hydrogen-bonding “fingers” are more powerful than ammonium groups, and the benzylamine series is superior over the anilinium series (vide infra). The new ligands easily distinguish between RNA and various DNA types, and produce characteristic changes in UV-vis-, fluorescence-, CD- as well as NMR spectra. Especially extended oligonucleotides of more than 100 base pairs are bound with affinities increasing from RNA (10 M Kd) < AT-rich (1 M) < GC-rich DNA double strands (100-10 nM). Ethidium bromide displacement studies strictly confirm this order, wich correlates well with relative sterical accessability of the respective nucleic acid’s major groove. CE50 values are remarkably low (1-4 M), more than 300 times lower than that of spermine, a typical backbone binder. Stoichiometries are rather high (1 calixarene dimer : 2 BP), suggesting a potential aggregation of bound ligands inside the spacious major groove. Most UV-vis melting curves display an inverted shape, and start from drastically enhanced absorption intensities for the DNA complexes. One obvious explanation would be direct hydrogen bond interaction between the calixarene cations and the nucleic base chromophores, which would also agree with the observed strongly increased inflection temperatures – most likely pointing to duplex stabilization. DAPI displacement follows a peculiar path of CD shifts: up to 1 equivalent of calixarene dimer can be accomodated in the dye-loaded DNA double strand, before displacement begins, ruling out minor groove insertion. Intriguingly, RNA complexation by calixarene dimers is accompanied with a drastic CD spectral transition from the typical A-form to a perfect B-signature, providing further experimental evidence for major groove binding. The orientation of the ligands can be deduced from NMR titrations, which feature simultaneous chemical shift changes and line broadening in the aromatic region of the calixarene, while the alkoxy tails remain unaltered. Obviously, the calixarene head penetrates deeply into the major groove, while the butoxy tails point out of the groove, and undergo hydrophobic interactions with neighbouring ligands without losing their flexibility. This binding mode is finally reproduced in all lowest energy conformations from force-field calculations on 1:1 complexes between double-stranded DNA dodecamers and calixarene dimers in water.

Izvorni jezik

Znanstvena područja
Kemija, Temeljne medicinske znanosti


Projekt / tema
098-0982464-2514 - Uloga različitih mehanizama odgovora stanica na terapiju oštećenjem DNA (Marijeta Kralj, )
098-0982914-2918 - Dizajn, sinteza i ispitivanje interakcija malih molekula s DNA, RNA i proteinima (Ivo Piantanida, )

Institut "Ruđer Bošković", Zagreb

Časopis indeksira:

  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus