Wittmann, C, Bacher, F, Enyedy, EA, Dömötör, O, Spengler, G, Madejski, C, Reynisson, J and Arion, VB (2022) Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile. Journal of Medicinal Chemistry, 65 (3). 2238 - 2261. ISSN 1520-4804

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Abstract

A series of latonduine and indoloquinoline derivatives HL1-HL8 and their copper(II) complexes (1-8) were synthesized and comprehensively characterized. The structures of five compounds (HL6, [CuCl(L1)(DMF)]·DMF, [CuCl(L2)(CH3OH)], [CuCl(L3)]·0.5H2O, and [CuCl2(H2L5)]Cl·2DMF) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC50 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 HL4 and 4 as well as HL8 and 8 induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. HL8 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.

Item Type: Article
Additional Information: The final version of this article and all relevant information related to it, including copyrights, can be found on the publisher website at; https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01740
Subjects: R Medicine > R Medicine (General)
R Medicine > R Medicine (General) > R735 Medical education. Medical schools. Research
R Medicine > RM Therapeutics. Pharmacology
Related URLs:
Depositing User: Symplectic
Date Deposited: 24 Feb 2022 08:46
Last Modified: 20 Jul 2022 13:40
URI: https://eprints.keele.ac.uk/id/eprint/10642

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