Affinity of the anthracycline antitumor drugsDoxorubicin and Sabarubicin for human telomeric G-quadruplex structures

Abstract

Combining various techniques in solution we proved that Doxorubicin, also called Adriamycin, and Sabarubicin, also known as MEN 10755, bind to the human telomeric sequence, 5'-d[GGG(TTAGGG)(3)]-3' (21-mer), assuming a G-quadruplex structure in the presence of K(+). Complexes of drugs with the 21-mer in 1 : 1 and 2 : 1 stoichiometry coexist in solution. Association constants were obtained from titration experiments and confirmed by isothermal titration calorimetry. The fluorescence of the drugs was quenched upon complexation. UV circular dichroism (CD) spectra of the complexes were characterized by the G-quadruplex signal and indicated that drug binding influences the equilibrium between quadruplex conformations. The visible CD spectra were exclusively due to the drug and show differences in the complexation modes of the two drugs. Spectroscopic and thermodynamic parameters of the 1 : 1 complexes point to drug stacking with the G-quadruplex top or bottom tetrad. Thermodynamic data suggests that the binding of the second drug molecule in the 2 : 1 complex may occur in a groove. Complexation caused a small increase in the thermal stability of the G-quadruplex main conformation, shifting T(m) from 62 to 67 °C.

Spectroscopic studies of anthracyclines: Structural characterization and in vitro tracking

“…Anthracyclines, especially DNR and DOX have been widely investigated using various spectroscopic methods, e.g. Raman spectroscopy [24,25], Resonance Raman (RR) [26][27][28], Surface Enhanced Raman Spectroscopy (SERS) [29][30][31][32], UV-Vis absorption [26,33] and FT-IR absorption spectroscopy [24,34,35]. The visible absorption spectra of DOX and DNR are, however, almost identical, having a maximum of absorption near to 480-490 nm.…”

Ultrafast Electron Transfer in Complexes of Doxorubicin with Human Telomeric G‐Quadruplexes and GC Duplexes Probed by Femtosecond Fluorescence Spectroscopy

“…However, it has been observed that doxorubicin (DOX; Scheme ), which is a natural anthracycline compound, can also cause telomere dysfunction for some cellular lines; this effect might arise from the ability of the drug to interact with telomeric G4 . In this respect, it was shown that DOX can form complexes with the human telomeric G4 sequence, 5′‐d[GGG(TTAGGG) 3 ]‐3′ (Tel21), with a comparable affinity to that for B‐DNA ,…”

A pyrene-imidazolium derivative that selectively Recognizes G-Quadruplex DNA

“…Among the various types of secondary structures in human DNA, such as B-DNA, Z-DNA, hair pins, etc [5]., guanine rich sequences like, G-quadruplexes serve an important role in cancer cell growth and control gene expression in telomeres [6]. G-quadruplexes are composed of four stranded guanine bases stabilized by monovalent cations such as Na þ or K þ between tetrad guanine bases [7]. Recent studies show that this unique structure can be formed not only in the telomeric region of the genome, but also among other guanine rich sequences having the potential to form quadruplex elsewhere in the human genome [8,9].…”