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

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.

SUBMITTER: Wittmann C 

PROVIDER: S-EPMC8842277 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature