posted on 2022-02-01, 19:07authored byChristopher Wittmann, Felix Bacher, Eva A. Enyedy, Orsolya Dömötör, Gabriella Spengler, Christian Madejski, Jóhannes Reynisson, Vladimir B. Arion
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.