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.

CICS UBI Centro de Investigação em Ciências da Saúde Universidade da Beira Interior Av Infante D Henrique 6200 506 Covilhã Portugal

CQE and Departamento de Engenharia Química Instituto Superior Técnico Universidade de Lisboa 1049 001 Lisboa Portugal

LAQV REQUIMTE and Department of Chemistry University of Aveiro 3810 193 Aveiro Portugal

Univ Bordeaux ARNA Laboratory INSERM U1212 CNRS UMR 5320 IECB F 33600 Pessac France

Univ Bordeaux ARNA Laboratory INSERM U1212 CNRS UMR 5320 IECB F 33600 Pessac France; Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 612 65 Brno Czech Republic

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G-Quadruplex Aptamer-Ligand Characterization