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

A series of latonduine and indoloquinoline derivatives HL ¹ - HL ⁸ and their copper(II) complexes ( 1-8 ) were synthesized and comprehensively characterized. The structures of five compounds ( HL ⁶ , [CuCl(L ¹ )(DMF)]·DMF , [CuCl(L ² )(CH ₃ OH)] , [CuCl(L ³ )]·0.5H ₂ O , and [CuCl ₂ (H ₂ L ⁵ )]Cl·2DMF ) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC ₅₀ 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 ⁴ and 4 as well as HL ⁸ 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 ⁸ 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.