Copper(II) complexes of indolo[2,3-c]quinoline-derived Schiff bases: Insight into the mechanism of their antiproliferative activity

Felix Bacher; Christian Madejski; Irina Kuznetcova; Orsolya Dömötör; Béla Gyurcsik; Zeyad H. Nafaee; Nóra Igaz; Csenge Bocz; Bálint Péntek; Mónika Kiricsi; Petra Raptova; Alexandru-Constantin Stoica; Michaela Hejl; Michael A. Jakupec; Samah Mutasim Alfadul; Maria V. Babak; Peter Rapta; Jóhannes Reynisson; Lenka Sindlerova; Éva A. Enyedy; Ernest Hamel; Vladimir B. Arion

doi:10.1016/j.ejmech.2026.118882

Copper(II) complexes of indolo[2,3-c]quinoline-derived Schiff bases: Insight into the mechanism of their antiproliferative activity

Felix Bacher^*
, Christian Madejski
, Irina Kuznetcova
, Orsolya Dömötör
, Béla Gyurcsik
, Zeyad H. Nafaee
, Nóra Igaz
, Csenge Bocz
, Bálint Péntek
, Mónika Kiricsi
, Petra Raptova
, Alexandru-Constantin Stoica
, Michaela Hejl
, Michael A. Jakupec
, Samah Mutasim Alfadul
, Maria V. Babak
, Peter Rapta
, Jóhannes Reynisson
, Lenka Sindlerova
, Éva A. Enyedy^*

Ernest Hamel, Vladimir B. Arion^*

^*Corresponding author for this work

Department of Chemistry

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

1 Citation (Scopus)

Abstract

Indoloquinolines are potent anticancer agents, but their poor aqueous solubility prevents clinical development. Indoloquinoline-based metal complexes offer an opportunity to circumvent this drawback. A series of new indolo[2,3-c]quinoline derivatives HL¹–HL⁸ and their copper(II) complexes were synthesized, comprehensively characterized and tested for antiproliferative activity against MDA-MB-231, MCF-7, MCF-7 KCR, A549 and DU-145 cancer cells and compared to known isomeric indolo[3,2-c]quinolines (HL¹¹–HL¹⁴ and 11–14). The Cu(II) complexes were generally as active, or slightly more so, than the proligands. Lead compounds HL⁸ and 8 showed superior anticancer activity compared to isomers HL¹⁴ and 14, respectively. Complex 8 was superior to HL⁸ in ROS generation in A549 cells, induced mitochondrial dysfunction as evidenced by JC-1 staining, induced lactate dehydrogenase release in medium, inhibited DNA synthesis and triggered apoptosis. DNA-binding studies, supported by molecular docking calculations, showed strong affinity of the compounds for double stranded DNA, to which they bind by intercalation. © 2026 The Authors.

Original language	English
Article number	118882
Number of pages	26
Journal	European Journal of Medicinal Chemistry
Volume	315
Online published	21 Apr 2026
DOIs	https://doi.org/10.1016/j.ejmech.2026.118882
Publication status	Online published - 21 Apr 2026

Funding

This work was funded by the Austrian Science Fund (FWF) grant no. P31293, by a grant from the Romanian National Authority for Research, project no. PNRR–III–C9-2023-I8-99 within the National Recovery and Resilience Plan, by the Slovak Research and Development Agency under contract nos APVV-23-0195, SK-HU-24-0003 (P. R.) and the grant agency VEGA (contract no. 1/0392/24), as well as by the National Research, Development and Innovation Office-NKFIA (Hungary) through projects TKP2021-EGA-32, K138318 and PharmaLab (RRF-2.3.1.-21-2022-00015). MTT experiments were performed using support from the City University of Hong Kong (Project No. 7005829).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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10.1016/j.ejmech.2026.118882

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Bacher, F., Madejski, C., Kuznetcova, I., Dömötör, O., Gyurcsik, B., Nafaee, Z. H., Igaz, N., Bocz, C., Péntek, B., Kiricsi, M., Raptova, P., Stoica, A.-C., Hejl, M., Jakupec, M. A., Alfadul, S. M., Babak, M. V., Rapta, P., Reynisson, J., Sindlerova, L., ... Arion, V. B. (2026). Copper(II) complexes of indolo[2,3-c]quinoline-derived Schiff bases: Insight into the mechanism of their antiproliferative activity. European Journal of Medicinal Chemistry, 315, Article 118882. Advance online publication. https://doi.org/10.1016/j.ejmech.2026.118882

@article{67fede89023a46faae87a05e5fb2be73,

title = "Copper(II) complexes of indolo[2,3-c]quinoline-derived Schiff bases: Insight into the mechanism of their antiproliferative activity",

abstract = "Indoloquinolines are potent anticancer agents, but their poor aqueous solubility prevents clinical development. Indoloquinoline-based metal complexes offer an opportunity to circumvent this drawback. A series of new indolo[2,3-c]quinoline derivatives HL1–HL8 and their copper(II) complexes were synthesized, comprehensively characterized and tested for antiproliferative activity against MDA-MB-231, MCF-7, MCF-7 KCR, A549 and DU-145 cancer cells and compared to known isomeric indolo[3,2-c]quinolines (HL11–HL14 and 11–14). The Cu(II) complexes were generally as active, or slightly more so, than the proligands. Lead compounds HL8 and 8 showed superior anticancer activity compared to isomers HL14 and 14, respectively. Complex 8 was superior to HL8 in ROS generation in A549 cells, induced mitochondrial dysfunction as evidenced by JC-1 staining, induced lactate dehydrogenase release in medium, inhibited DNA synthesis and triggered apoptosis. DNA-binding studies, supported by molecular docking calculations, showed strong affinity of the compounds for double stranded DNA, to which they bind by intercalation. {\textcopyright} 2026 The Authors.",

author = "Felix Bacher and Christian Madejski and Irina Kuznetcova and Orsolya D{\"o}m{\"o}t{\"o}r and B{\'e}la Gyurcsik and Nafaee, \{Zeyad H.\} and N{\'o}ra Igaz and Csenge Bocz and B{\'a}lint P{\'e}ntek and M{\'o}nika Kiricsi and Petra Raptova and Alexandru-Constantin Stoica and Michaela Hejl and Jakupec, \{Michael A.\} and Alfadul, \{Samah Mutasim\} and Babak, \{Maria V.\} and Peter Rapta and J{\'o}hannes Reynisson and Lenka Sindlerova and Enyedy, \{{\'E}va A.\} and Ernest Hamel and Arion, \{Vladimir B.\}",

year = "2026",

month = apr,

day = "21",

doi = "10.1016/j.ejmech.2026.118882",

language = "English",

volume = "315",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

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Bacher, F, Madejski, C, Kuznetcova, I, Dömötör, O, Gyurcsik, B, Nafaee, ZH, Igaz, N, Bocz, C, Péntek, B, Kiricsi, M, Raptova, P, Stoica, A-C, Hejl, M, Jakupec, MA, Alfadul, SM , Babak, MV, Rapta, P, Reynisson, J, Sindlerova, L, Enyedy, ÉA, Hamel, E & Arion, VB 2026, 'Copper(II) complexes of indolo[2,3-c]quinoline-derived Schiff bases: Insight into the mechanism of their antiproliferative activity', European Journal of Medicinal Chemistry, vol. 315, 118882. https://doi.org/10.1016/j.ejmech.2026.118882

Copper(II) complexes of indolo[2,3-c]quinoline-derived Schiff bases: Insight into the mechanism of their antiproliferative activity. / Bacher, Felix; Madejski, Christian; Kuznetcova, Irina et al.
In: European Journal of Medicinal Chemistry, Vol. 315, 118882, 05.10.2026.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Copper(II) complexes of indolo[2,3-c]quinoline-derived Schiff bases

T2 - Insight into the mechanism of their antiproliferative activity

AU - Bacher, Felix

AU - Madejski, Christian

AU - Kuznetcova, Irina

AU - Dömötör, Orsolya

AU - Gyurcsik, Béla

AU - Nafaee, Zeyad H.

AU - Igaz, Nóra

AU - Bocz, Csenge

AU - Péntek, Bálint

AU - Kiricsi, Mónika

AU - Raptova, Petra

AU - Stoica, Alexandru-Constantin

AU - Hejl, Michaela

AU - Jakupec, Michael A.

AU - Alfadul, Samah Mutasim

AU - Babak, Maria V.

AU - Rapta, Peter

AU - Reynisson, Jóhannes

AU - Sindlerova, Lenka

AU - Enyedy, Éva A.

AU - Hamel, Ernest

AU - Arion, Vladimir B.

PY - 2026/4/21

Y1 - 2026/4/21

N2 - Indoloquinolines are potent anticancer agents, but their poor aqueous solubility prevents clinical development. Indoloquinoline-based metal complexes offer an opportunity to circumvent this drawback. A series of new indolo[2,3-c]quinoline derivatives HL1–HL8 and their copper(II) complexes were synthesized, comprehensively characterized and tested for antiproliferative activity against MDA-MB-231, MCF-7, MCF-7 KCR, A549 and DU-145 cancer cells and compared to known isomeric indolo[3,2-c]quinolines (HL11–HL14 and 11–14). The Cu(II) complexes were generally as active, or slightly more so, than the proligands. Lead compounds HL8 and 8 showed superior anticancer activity compared to isomers HL14 and 14, respectively. Complex 8 was superior to HL8 in ROS generation in A549 cells, induced mitochondrial dysfunction as evidenced by JC-1 staining, induced lactate dehydrogenase release in medium, inhibited DNA synthesis and triggered apoptosis. DNA-binding studies, supported by molecular docking calculations, showed strong affinity of the compounds for double stranded DNA, to which they bind by intercalation. © 2026 The Authors.

AB - Indoloquinolines are potent anticancer agents, but their poor aqueous solubility prevents clinical development. Indoloquinoline-based metal complexes offer an opportunity to circumvent this drawback. A series of new indolo[2,3-c]quinoline derivatives HL1–HL8 and their copper(II) complexes were synthesized, comprehensively characterized and tested for antiproliferative activity against MDA-MB-231, MCF-7, MCF-7 KCR, A549 and DU-145 cancer cells and compared to known isomeric indolo[3,2-c]quinolines (HL11–HL14 and 11–14). The Cu(II) complexes were generally as active, or slightly more so, than the proligands. Lead compounds HL8 and 8 showed superior anticancer activity compared to isomers HL14 and 14, respectively. Complex 8 was superior to HL8 in ROS generation in A549 cells, induced mitochondrial dysfunction as evidenced by JC-1 staining, induced lactate dehydrogenase release in medium, inhibited DNA synthesis and triggered apoptosis. DNA-binding studies, supported by molecular docking calculations, showed strong affinity of the compounds for double stranded DNA, to which they bind by intercalation. © 2026 The Authors.

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UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-105039861726&origin=recordpage

U2 - 10.1016/j.ejmech.2026.118882

DO - 10.1016/j.ejmech.2026.118882

M3 - RGC 21 - Publication in refereed journal

SN - 0223-5234

VL - 315

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 118882

ER -

Copper(II) complexes of indolo[2,3-c]quinoline-derived Schiff bases: Insight into the mechanism of their antiproliferative activity

Abstract

Funding

UN SDGs

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