@article{81bafcd27dd64d41b8167cc3fe70162b,
title = "Diketopyrrolo[3,4-c]pyrrole derivative as a promising ligand for the stabilization of G-quadruplex DNA structures",
abstract = "Telomerase, oncogenes and tumor suppressors are closely associated with tumour occurrence, therefore these structures are being recognized as targets for the development of new anticancer drugs. The efficacy of several molecules in telomerase inhibition and regulation of genes expression, by adduct formation with G-quadruplexes (G4), has been studied by biophysical and biochemical methods with promising results. We report here the synthesis and structural characterization of a small positively charged diketopyrrolo[3,4–c]pyrrole derivative, identified as DPP(PyMe)2, that showed very promising results as G4 stabilizing ligand. The data obtained from UV–Vis and fluorescence experiments suggest that DPP(PyMe)2 presents high affinity to G4 structures. Docking studies and molecular dynamics simulations unraveled the binding modes of the ligand with four G4 structures. The obtained results also allowed us to conclude that the DPP(PyMe)2 ligand binds into the top G-tetrad or in a mixed binding mode depending on the GQ structure. A remarkable selectivity of DPP(PyMe)2 for c-MYC and KRAS 32R in the presence of ds26 was observed by circular dichroism (CD) and fluorescence resonance energy transfer (FRET) melting experiments. CD titrations revealed a stabilization higher than 30 °C in the case of c-MYC G4 structure and, for the same sequence, DPP(PyMe)2 showed the ability to block the activity of Taq polymerase in a dose-dependent manner. The subcellular localization obtained with confocal microscopy corroborates the results obtained by the other techniques and the obtained data suggest that DPP(PyMe)2 is an attractive ligand for the development of G4 labelling probes.",
keywords = "G-quadruplexes, G4 ligands, Loop/groove, Mixed binding mode, Oncogene promoters, telomeric G4",
author = "Ramos, {Catarina I.V.} and Almod{\^o}var, {Vitor A.S.} and Candeias, {Nuno R.} and Tiago Santos and Carla Cruz and Neves, {M. Gra{\c c}a P.M.S.} and Tom{\'e}, {Augusto C.}",
note = "Funding Information: The authors are grateful to the University of Aveiro and to Funda??o para a Ci?ncia e a Tecnologia (FCT) for the financial support to LAQV-REQUIMTE (Ref.UIDB/50006/2020), CICS-UBI research unit (Ref. UIDB/00709/2020) and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement. CSC?IT Center for Science Ltd, Finland, is acknowledged for the allocation of computational resources. Catarina I.V. Ramos acknowledges FCT for her contract 047-88-ARH/2018. Vitor Almodovar thanks FCT for his doctoral grant (SFRH/BD/135598/2018). Nuno Candeias acknowledges FCT for financial support (CEE-CINST/2018). Tiago Santos acknowledges FCT for the doctoral fellowship PD/BD/142851/2018 integrated in the Ph.D. Programme in NMR applied to chemistry, materials and biosciences (PD/00065/2013). This work was supported by project IF/00959/2015 financed by Fundo Social Europeu e Programa Operacional Potencial Humano and C. Cruz acknowledges the project FCT ref. UIDP/00709/2020. Funding Information: Tiago Santos acknowledges FCT for the doctoral fellowship PD/BD/142851/2018 integrated in the Ph.D. Programme in NMR applied to chemistry, materials and biosciences (PD/00065/2013). This work was supported by project IF/00959/2015 financed by Fundo Social Europeu e Programa Operacional Potencial Humano and C. Cruz acknowledges the project FCT ref. UIDP/00709/2020. Funding Information: The authors are grateful to the University of Aveiro and to Funda{\c c}{\~a}o para a Ci{\^e}ncia e a Tecnologia (FCT) for the financial support to LAQV-REQUIMTE (Ref.UIDB/50006/2020), CICS-UBI research unit (Ref. UIDB/00709/2020) and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement. CSC–IT Center for Science Ltd, Finland, is acknowledged for the allocation of computational resources. Catarina I.V. Ramos acknowledges FCT for her contract 047-88-ARH/2018. Vitor Almodovar thanks FCT for his doctoral grant (SFRH/BD/135598/2018). Nuno Candeias acknowledges FCT for financial support (CEE-CINST/2018). Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = may,
doi = "10.1016/j.bioorg.2022.105703",
language = "English",
volume = "122",
journal = "BIOORGANIC CHEMISTRY",
issn = "0045-2068",
publisher = "Academic Press Inc.",
}