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Molecular recognition in naphthoquinone derivatives - G-quadruplex complexes by NMR

B. Riva ; Raphael Ferreira (Institutionen för biologi och bioteknik, Systembiologi) ; L. Musso ; R. Artali ; L. Scaglioni ; S. Mazzini
Biochimica Et Biophysica Acta-General Subjects (0304-4165). Vol. 1850 (2015), 4, p. 673-680.
[Artikel, refereegranskad vetenskaplig]

Background: G-quadruplexes have become important drug-design targets for the treatment of various human disorders such as cancer, diabetes and cardiovascular diseases. Recently, G-quadruplex structures have been visualized in the DNA of human cells and appeared to be dynamically sensitive to the cell cycle and stabilized by small molecule ligands. A small library of isoxazolo naphthoquinones (1a-h), which exhibited a strong antiproliferafive activity on different cancer cell lines, was studied as potential ligands of G-quadruplex DNA. Methods: The DNA binding properties of a series of the selected compounds have been analyzed by fluorescence assays. NMR/modeling studies were performed to describe the complexes between G-quadruplex DNA sequences and two selected compounds 1a and 1b. Results: 1a and 1b in the presence of G-quadruplexes, d(T(2)AG(3)T)(4), d(TAG(3)T(2)A)(4) and d(T(2)G(3)T(2))(4), showed good ability of intercalation and the formation of complexes with 2:1 stoichiometry. 1a showed an important interaction with the sequence Pu22 belonging to the promoter of oncogenes c-myc. Conclusions: The ligands directly interact with the external G-tetrads of the G-quadruplexes, without alterations in the structure of the G-quadruplex core. The role of the adenine moieties over the G-tetrads in the stabilization of the complexes was discussed. General significance: The results obtained suggested that the strong antiproliferative activity of isoxazolo naphthoquinones is not due to the Hsp90 inhibition, but mainly to the interaction at the level of telomeres and/or at the level of gene promoter. These findings can be used as a basis for the rational drug design of new anticancer agents.

Nyckelord: G-quadruplex, NMR studies, DNA-binding drugs, Isoxazolo naphthoquinone, Molecular modeling



Denna post skapades 2015-03-26.
CPL Pubid: 214364

 

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Institutioner (Chalmers)

Institutionen för biologi och bioteknik, Systembiologi

Ämnesområden

Biofysik
Bioinformatik och systembiologi

Chalmers infrastruktur