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

• Published in: Journal of medicinal chemistry Vol. 65; no. 3; pp. 2238 - 2261
• Main Authors: Wittmann, Christopher, Bacher, Felix, Enyedy, Eva A, Dömötör, Orsolya, Spengler, Gabriella, Madejski, Christian, Reynisson, Jóhannes, Arion, Vladimir B
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.02.2022; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Binding Sites; Cattle; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Coordination Complexes - chemistry; Coordination Complexes - metabolism; Coordination Complexes - pharmacology; Coordination Complexes - therapeutic use; Copper - chemistry; Crystallography, X-Ray; DNA - chemistry; DNA - metabolism; Heterocyclic Compounds, 3-Ring - chemistry; Humans; Indoles - chemistry; Life Sciences & Biomedicine; Molecular Conformation; Molecular Docking Simulation; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Kinases - chemistry; Protein Kinases - metabolism; Quinolines - chemistry; Science & Technology; Solubility; Structure-Activity Relationship; FREE-RADICAL UNIT; SIGNALING PATHWAYS; ARENE COMPLEXES; PAULLONES; GLIOBLASTOMA-MULTIFORME; PROTEIN-LIGAND DOCKING; EMPIRICAL SCORING FUNCTIONS; CANCER; MM3 FORCE-FIELD; MOLECULAR-MECHANICS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01740

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.