Diketopyrrolo[3,4-c]pyrrole derivative as a promising ligand for the stabilization of G-quadruplex DNA structures

Catarina I.V. Ramos; Vitor A.S. Almodôvar; Nuno R. Candeias; Tiago Santos; Carla Cruz; M. Graça P.M.S. Neves; Augusto C. Tomé

doi:10.1016/j.bioorg.2022.105703

Diketopyrrolo[3,4-c]pyrrole derivative as a promising ligand for the stabilization of G-quadruplex DNA structures

Catarina I.V. Ramos, Vitor A.S. Almodôvar, Nuno R. Candeias, Tiago Santos, Carla Cruz, M. Graça P.M.S. Neves, Augusto C. Tomé

Materials Science and Environmental Engineering

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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.

Original language	English
Article number	105703
Journal	BIOORGANIC CHEMISTRY
Volume	122
DOIs	https://doi.org/10.1016/j.bioorg.2022.105703
Publication status	Published - May 2022
Publication type	A1 Journal article-refereed

Funding

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. 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. The authors are grateful to the University of Aveiro and to Fundação para a Ciência 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).

Keywords

G-quadruplexes
G4 ligands
Loop/groove
Mixed binding mode
Oncogene promoters
telomeric G4

Publication forum classification

Publication forum level 1

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Drug Discovery
Organic Chemistry

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10.1016/j.bioorg.2022.105703

Bioorg Chem 122 (2022) 105703Accepted author manuscript, 2.14 MBLicence: CC BY-NC-ND

https://urn.fi/URN:NBN:fi:tuni-202302152377Licence: CC BY-NC-ND

Cite this

@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.",

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TY - JOUR

T1 - Diketopyrrolo[3,4-c]pyrrole derivative as a promising ligand for the stabilization of G-quadruplex DNA structures

AU - Ramos, Catarina I.V.

AU - Almodôvar, Vitor A.S.

AU - Candeias, Nuno R.

AU - Santos, Tiago

AU - Cruz, Carla

AU - Neves, M. Graça P.M.S.

AU - Tomé, Augusto C.

N1 - 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 Fundação para a Ciência 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: © 2022 Elsevier Inc.

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

KW - G-quadruplexes

KW - G4 ligands

KW - Loop/groove

KW - Mixed binding mode

KW - Oncogene promoters

KW - telomeric G4

U2 - 10.1016/j.bioorg.2022.105703

DO - 10.1016/j.bioorg.2022.105703

M3 - Article

AN - SCOPUS:85125559865

SN - 0045-2068

VL - 122

JO - BIOORGANIC CHEMISTRY

JF - BIOORGANIC CHEMISTRY

M1 - 105703

ER -

Diketopyrrolo[3,4-c]pyrrole derivative as a promising ligand for the stabilization of G-quadruplex DNA structures

Abstract

Funding

Keywords

Publication forum classification

ASJC Scopus subject areas

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