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

Reynisson

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, GSK3ß, 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.

Citation

Reynisson. (2022). Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile. Journal of Medicinal Chemistry, 2238 - 2261. https://doi.org/10.1021/acs.jmedchem.1c01740

• Journal Article Type: Article
• Acceptance Date: Feb 1, 2022
• Publication Date: Feb 1, 2022
• Publicly Available Date: Feb 24, 2022
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Publisher: American Chemical Society
• Pages: 2238 - 2261
• DOI: https://doi.org/10.1021/acs.jmedchem.1c01740
• Public URL: https://keele-repository.worktribe.com/output/422414
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01740