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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Binding Sites
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Cattle
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Coordination Complexes / chemistry*
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Coordination Complexes / metabolism
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Coordination Complexes / pharmacology
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Coordination Complexes / therapeutic use
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Copper / chemistry*
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Crystallography, X-Ray
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DNA / chemistry
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DNA / metabolism
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Heterocyclic Compounds, 3-Ring / chemistry*
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Humans
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Indoles / chemistry
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Molecular Conformation
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Molecular Docking Simulation
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein Kinases / chemistry
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Protein Kinases / metabolism
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Quinolines / chemistry*
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Solubility
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Coordination Complexes
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Heterocyclic Compounds, 3-Ring
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Indoles
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Protein Kinase Inhibitors
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Quinolines
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latonduine A
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Copper
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DNA
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calf thymus DNA
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Protein Kinases