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

Abstract

The new bis-phenanthridine triamine is characterised by three pK(a) values: 3.65; 6.0 and >7.5. A significant difference in the protonation state of at pH = 5 (four positive charges) and at pH = 7 (less than two positive charges) accounts for the strong dependence of -nucleotide binding constants on nucleotide charge under acidic conditions, whereas at neutral pH all -nucleotide complexes are of comparable stability. All experimental data point at intercalation as the dominant binding mode of 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 is significantly higher at pH = 5 than at neutral conditions. This is not the case with poly dA-poly dT, indicating that the specific secondary structure of the latter, most likely the shape of the minor groove, plays a key role in complex stability. At pH = 5 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 compared to its "monomer" can be accounted for by cooperative action of two phenanthridinium units and the 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.

Novel bis-phenanthridine derivatives with easily tunable linkers, study of their interactions with DNA and screening of antiproliferative activity

“…The advantages in respect to commonly used synthesis [11,12,15] were demonstrated by easy and efficient modulation of bis-phenanthridine structure starting from the only two building blocks (glycine and phenanthridine-L-alanine), which allowed simple tuning of the cavity size between phenanthridine subunits as well as intramolecular rigidity of compounds. Spectrophotometric studies revealed that in biologically relevant medium bisphenanthridine derivatives exhibit significant intramolecular interactions strongly dependent on the rigidity and length of the peptide linker.…”

“…[12] Our recent results have pointed out that selectivity of bis-phenanthridine derivatives toward various DNA/RNA sequences could be controlled by the steric effects [13,14] or by electrostatic interactions with DNA/RNA backbone and/or nucleobases. [15,16] However, the efforts to upgrade already promising molecules quite often led to longer and more complicated synthetic pathways. Therefore, the strategy of convergent synthesis, which will retain structural features of successful molecules but allow significantly easier and faster modulation of active structure, would allow fine tuning of selectivity and/or other tasks of a novel, small molecules to be done by reasonable time and effort investment.…”

Synthesis, GC selective DNA binding and topoisomerase II inhibition activities of ruthenium(II) polypyridyl complex containing 11-aminopteridino[6,7-f][1,10]phenanthrolin-13(12H)-one

“…The absorbance at 260 nm was continuously monitored for solutions of each DNA (100 lM) in the absence and presence of different concentration of [Ru(bpy) 2 (appo)] 2+ in SSC buffer (150 mM NaCl, 15 mM sodium citrate, pH 7.0) for CT-DNA and SC buffer (15 mM sodium citrate, pH 7.0) for poly(dA) Á poly(dT) and poly(dG) Á poly(dC) [35,36]. The temperature of the each sample was increased by 1.0°C min À1 for CT-DNA and 0.5°C min À1 for poly(dA) Á poly(dT) and poly(dG) Á poly(dC).…”

The phenanthridine biguanides efficiently differentiate between dGdC, dAdT and rArU sequences by two independent, sensitive spectroscopic methods

“…15 In our very recent studies, we noticed that electron-rich substituent as urea attached at 8-position of phenanthridine can induce intriguing fluorimetric specificity against AT (emission increase) and GC (emission quenching) basepairs, which was not previously reported for phenanthridine derivatives. 16 All aforementioned inspired us to design novel phenanthridine derivatives equipped at 3 and/or 8 positions with substituents which can actively participate in non-covalent binding to DNA/RNA, due to steric and electronic properties differentiate between various secondary structures and/or basepair composition of polynucleotide and report that recognition in the spectroscopically feasible form.…”