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Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile

[Image: see text] A series of latonduine and indoloquinoline derivatives HL(1)–HL(8) and their copper(II) complexes (1–8) were synthesized and comprehensively characterized. The structures of five compounds (HL(6), [CuCl(L(1))(DMF)]·DMF, [CuCl(L(2))(CH(3)OH)], [CuCl(L(3))]·0.5H(2)O, and [CuCl(2)(H(2...

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Autores principales: Wittmann, Christopher, Bacher, Felix, Enyedy, Eva A., Dömötör, Orsolya, Spengler, Gabriella, Madejski, Christian, Reynisson, Jóhannes, Arion, Vladimir B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842277/
https://www.ncbi.nlm.nih.gov/pubmed/35104137
http://dx.doi.org/10.1021/acs.jmedchem.1c01740
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author Wittmann, Christopher
Bacher, Felix
Enyedy, Eva A.
Dömötör, Orsolya
Spengler, Gabriella
Madejski, Christian
Reynisson, Jóhannes
Arion, Vladimir B.
author_facet Wittmann, Christopher
Bacher, Felix
Enyedy, Eva A.
Dömötör, Orsolya
Spengler, Gabriella
Madejski, Christian
Reynisson, Jóhannes
Arion, Vladimir B.
author_sort Wittmann, Christopher
collection PubMed
description [Image: see text] A series of latonduine and indoloquinoline derivatives HL(1)–HL(8) and their copper(II) complexes (1–8) were synthesized and comprehensively characterized. The structures of five compounds (HL(6), [CuCl(L(1))(DMF)]·DMF, [CuCl(L(2))(CH(3)OH)], [CuCl(L(3))]·0.5H(2)O, and [CuCl(2)(H(2)L(5))]Cl·2DMF) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC(50) values with promising selectivity toward human colon adenocarcinoma multidrug-resistant Colo320 cancer cells as compared to the doxorubicin-sensitive Colo205 cell line. The lead compounds HL(4) and 4 as well as HL(8) and 8 induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. HL(8) showed selective inhibition for the PIM-1 enzyme, while 8 revealed strong inhibition of five other enzymes, i.e., SGK-1, PKA, CaMK-1, GSK3β, and MSK1, from a panel of 50 kinases. Furthermore, molecular modeling of the ligands and complexes showed a good fit to the binding pockets of these targets.
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spelling pubmed-88422772022-02-15 Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile Wittmann, Christopher Bacher, Felix Enyedy, Eva A. Dömötör, Orsolya Spengler, Gabriella Madejski, Christian Reynisson, Jóhannes Arion, Vladimir B. J Med Chem [Image: see text] A series of latonduine and indoloquinoline derivatives HL(1)–HL(8) and their copper(II) complexes (1–8) were synthesized and comprehensively characterized. The structures of five compounds (HL(6), [CuCl(L(1))(DMF)]·DMF, [CuCl(L(2))(CH(3)OH)], [CuCl(L(3))]·0.5H(2)O, and [CuCl(2)(H(2)L(5))]Cl·2DMF) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC(50) values with promising selectivity toward human colon adenocarcinoma multidrug-resistant Colo320 cancer cells as compared to the doxorubicin-sensitive Colo205 cell line. The lead compounds HL(4) and 4 as well as HL(8) and 8 induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. HL(8) showed selective inhibition for the PIM-1 enzyme, while 8 revealed strong inhibition of five other enzymes, i.e., SGK-1, PKA, CaMK-1, GSK3β, and MSK1, from a panel of 50 kinases. Furthermore, molecular modeling of the ligands and complexes showed a good fit to the binding pockets of these targets. American Chemical Society 2022-02-01 2022-02-10 /pmc/articles/PMC8842277/ /pubmed/35104137 http://dx.doi.org/10.1021/acs.jmedchem.1c01740 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Wittmann, Christopher
Bacher, Felix
Enyedy, Eva A.
Dömötör, Orsolya
Spengler, Gabriella
Madejski, Christian
Reynisson, Jóhannes
Arion, Vladimir B.
Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile
title Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile
title_full Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile
title_fullStr Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile
title_full_unstemmed Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile
title_short Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile
title_sort highly antiproliferative latonduine and indolo[2,3-c]quinoline derivatives: complex formation with copper(ii) markedly changes the kinase inhibitory profile
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842277/
https://www.ncbi.nlm.nih.gov/pubmed/35104137
http://dx.doi.org/10.1021/acs.jmedchem.1c01740
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