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

Abstract

A series of latonduine and indoloquinoline derivatives <b>HL¹</b>-<b>HL⁸</b> and their copper(II) complexes (<b>1-8</b>) were synthesized and comprehensively characterized. The structures of five compounds (<b>HL⁶</b>, <b>[CuCl(L¹)(DMF)]·DMF</b>, <b>[CuCl(L²)(CH₃OH)]</b>, <b>[CuCl(L³)]·0.5H₂O</b>, and <b>[CuCl₂(H₂L⁵)]Cl·2DMF</b>) 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 <b>HL⁴</b> and <b>4</b> as well as <b>HL⁸</b> and <b>8</b> induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. <b>HL⁸</b> showed selective inhibition for the PIM-1 enzyme, while <b>8</b> 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.