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

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

  • J Med Chem. 2022 Feb 10;65(3):2238-2261. doi: 10.1021/acs.jmedchem.1c01740.
Christopher Wittmann 1,  Felix Bacher 1,  Eva A Enyedy 2 3,  Orsolya Dömötör 2 3,  Gabriella Spengler 3 4,  Christian Madejski 1,  Jóhannes Reynisson 5,  Vladimir B Arion 1
Affiliations

Affiliations

  • 1 Institute of Inorganic Chemistry of the University of Vienna, Währinger Strasse, 42, Vienna A1090, Austria.
  • 2 Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, Szeged H-6720, Hungary.
  • 3 MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, Szeged H-6720, Hungary.
  • 4 Department of Medical Microbiology, Albert Szent-Györgyi Health Center and Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6, Szeged H-6725, Hungary.
  • 5 School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, United Kingdom.
PMID: 35104137 DOI: 10.1021/acs.jmedchem.1c01740
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.

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