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A novel bis-phenanthridine triamine with pH controlled binding to nucleotides and nucleic acids


Malojčić, Goran; Piantanida, Ivo; Marinić, Mirna; Žinić, Mladen; Marjanović, Marko; Kralj, Marijeta; Pavelić, Krešimir; Schneider, Hans-Jörg
A novel bis-phenanthridine triamine with pH controlled binding to nucleotides and nucleic acids // Organic & biomolecular chemistry, 3 (2005), 4373 - 4382 (međunarodna recenzija, članak, znanstveni)


Naslov
A novel bis-phenanthridine triamine with pH controlled binding to nucleotides and nucleic acids

Autori
Malojčić, Goran ; Piantanida, Ivo ; Marinić, Mirna ; Žinić, Mladen ; Marjanović, Marko ; Kralj, Marijeta ; Pavelić, Krešimir ; Schneider, Hans-Jörg

Izvornik
Organic & biomolecular chemistry (1477-0520) 3 (2005); 4373 - 4382

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

Ključne riječi
DNA; RNA; intercalator; pH control

Sažetak
The new bis-phenanthridine triamine (3) is characterised by three pKa values: 3.65 ; 6.0 and >7.5. Significant difference in protonation state of 3 at pH = 5 (four positive charges) and at pH = 7 (less than two positive charges) accounts for strong dependence of 3/nucleotide binding constants on nucleotide charge under acidic conditions, whereas at neutral pH all 3/nucleotide complexes are of comparable stability. All experimental data point at intercalation as dominant binding mode of 3 to polynucleotides. However, there is no indication of bis-intercalation of the two phenanthridine subunits in binding to double stranded polynucleotides, the respective complexes being most likely mono-intercalative. Thermal stabilisation of calf thymus DNA (ct-DNA) and poly A-poly U duplexes upon addition of 3 is significantly higher at pH = 5 than at neutral conditions. This is not the case with poly dA-poly dT, indicating that specific secondary structure of the latter, most likely the shape of the minor groove, plays a key role in complex stability. At pH = 5 3 acts as a fluorimetric probe for poly G (emission quenching) as opposed to other ss-polynucleotides (emission increase), while at neutral conditions this specificity is lost. One order of magnitude higher cytotoxicity of 3 compared to its "monomer" 4 can be accounted for by cooperative action of two phenanthridinium units and charged triamine linker. The results presented here are of interest to the development of e.g. sequence-selective cytostatic drugs, and in particular for the possibility to control the drug activity properties over binding to DNA and/or RNA by variation of the pH of its surrounding.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Temeljne medicinske znanosti



POVEZANOST RADA


Projekt / tema
0098053
0098092

Ustanove
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
  • MEDLINE