Phthalocyanines for G-quadruplex aptamers binding

• Published in: Bioorganic chemistry 2020-07, Vol.100 (16), p.103920, Article 103920
• Main Authors: Lopes-Nunes, Jéssica, Carvalho, Josué, Figueiredo, Joana, Ramos, Catarina I.V., Lourenço, Leandro M.O., Tomé, João P.C., Neves, Maria G.P.M.S., Mergny, Jean-Louis, Queiroz, João A., Salgado, Gilmar F., Cruz, Carla
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Aptamers, Nucleotide - chemistry; Aptamers, Nucleotide - pharmacology; Biophysical characterization; Cell Line; Cell Survival - drug effects; Chemical Sciences; G-quadruplex aptamers; G-Quadruplexes; HeLa Cells; Humans; Indoles - chemistry; Indoles - pharmacology; Life Sciences; Molecular Docking Simulation; Neoplasms - drug therapy; Oligodeoxyribonucleotides - chemistry; Oligodeoxyribonucleotides - pharmacology; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Phthalocyanines
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103920

[Display omitted] •Zn(II)-phthalocyanine derivatives are proposed as ligands of G-quadruplex aptamers.•AS1411 and its derived sequences AT11, -L0 and -B0 are used to deliver the ligands.•Docking simulations suggest an end-stacking mode of interaction for the ligands.•ZnPc 4 presented the highest affinity and conformational changes on the G4 structures.•ZnPc 3 toxicity towards cancer cells was enhanced when complexed with G4 aptamers. The G-quadruplex (G4)-forming sequence within the AS1411 derivatives with alternative nucleobases and backbones can improve the chemical and biological properties of AS1411. Zn(II) phthalocyanine (ZnPc) derivatives have potential as high-affinity G4 ligands because they have similar size and shape to the G-quartets. The interactions of four Zn(II) phthalocyanines with the G4 AS1411 aptamer and its derivatives were determined by biophysical techniques, molecular docking and gel electrophoresis. Cell viability assay was carried out to evaluate the antiproliferative effects of Zn(II) phthalocyanines and complexes. CD experiments showed structural changes after addition of ZnPc 4, consistent with multiple binding modes and conformations shown by NMR and gel electrophoresis. CD melting confirmed that ZnPc 2 and ZnPc 4, both containing eight positive charges, are able to stabilize the AT11 G4 structure (ΔTm > 30 °C and 18.5 °C, respectively). Molecular docking studies of ZnPc 3 and ZnPc 4 suggested a preferential binding to the 3′- and 5′-end, respectively, of the AT11 G4. ZnPc 3 and its AT11 and AT11-L0 complexes revealed pronounced cytotoxic effect against cervical cancer cells and no cytotoxicity to normal human cells. Zn(II) phthalocyanines provide the basis for the development of effective therapeutic agents as G4 ligands.