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Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II)
Christopher Wittmann1, Felix Bacher1, Eva A Enyedy2,3
1Institute of Inorganic Chemistry of the University of Vienna, Währinger Strasse, 42, Vienna A1090, Austria.
Abstract:
A series of latonduine and indoloquinoline derivatives HL-HL and their copper(II) complexes (1-8) were synthesized and comprehensively characterized. The structures of five compounds (HL, [CuCl(L, [CuCl(L, [CuCl(L, and [CuCl) 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 HL and 4 as well as HL 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 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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