Affinity of the anthracycline antitumor drugs Doxorubicin and Sabarubicin for human telomeric G-quadruplex structures.
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.
Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, via Piero Gobetti 101, I-40129 Bologna, Italy. manet@isof.cnr.it
Ilse
I
Manet
Francesco
F
Manoli
Barbara
B
Zambelli
Giuseppina
G
Andreano
Annalisa
A
Masi
Luciano
L
Cellai
Sandra
S
Monti
D000970:Antineoplastic Agents / Q000737:chemistry*; D001483:Base Sequence; D002151:Calorimetry; D002942:Circular Dichroism; D004187:Disaccharides / Q000737:chemistry*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D009690:Nucleic Acid Conformation; D044367:Phase Transition; D011188:Potassium / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D016615:Telomere / Q000737:chemistry*; D013816:Thermodynamics; D044366:Transition Temperature
D000970:Antineoplastic Agents; D004187:Disaccharides; D004317:Doxorubicin; D011188:Potassium; C107602:sabarubicin