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 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.

Synthesis, structural studies, interaction with DNA/HSA and antitumor evaluation of new Cu(ii) complexes containing 2-(1H-imidazol-2-yl)pyridine and amino acids

“…3,4 Numerous studies have reported that copper complexes may have excellent anticancer activity and low toxicity owing to their different antitumor mechanisms from those of platinum-based chemotherapeutic drugs. 5,6 In addition, copper(II) complexes are prone to redox reactions under physiological conditions, and intracellular cytotoxic reactive oxygen species (ROS) will be generated by the mutual conversion of oxidized state (Cu 2+ ) and reduced state (Cu + ). 7,8 Therefore, copper(II) complexes are considered as potential candidates for anticancer therapy and medical applications.…”

Elucidation of Structure–Activity Relationships in Indolobenzazepine-Derived Ligands and Their Copper(II) Complexes: the Role of Key Structural Components and Insight into the Mechanism of Action

“…However, coordination of these ligands to copper(II) might induce a new mechanism of action. 48 In particular, fully distinct inhibitory profiles in enzyme inhibition assays were disclosed recently for indolo[3,2- c ]quinoline-based ligand and its copper(II) complex, 34 highlighting a special role of copper(II) in the underlying mechanism of cytotoxicity. The anticancer activity of copper(II) complexes 1 – 4 is mostly due to their redox activity (when compared to redox silent ligands HL 1 – HL 4 ) which resulted in the generation of cytotoxic ROS and induction of ER stress (vide infra).…”

“…The in vitro antiproliferative activity of novel organic compounds HL 1 −HL 4 and corresponding copper(II) complexes 1−4 was tested in the breast cancer cell line MDA-MB-231, hepatocellular carcinoma cell line LM3, and human embryonic kidney cell line HEK293 and then compared to those of the previously reported paullones HL 5 −HL 7 and copper(II) complexes 5−7, 39,44 as well as latonduines HL 8 −HL 11 and copper(II) complexes 8−11. 34 The two cancer cell lines were reported to exhibit quite aggressive behavior in patients, high rates of metastasis, and proliferation. 45,46 The in vitro anticancer activity was determined by the colorimetric MTT assay with an exposure time of 72 h. The IC 50 values of compounds of interest are listed in Table 1.…”

“…Previously, we showed that indolobenzazepines and structurally similar compounds formed monocationic complexes of 1:1 or 1:2 metal-to-ligand stoichiometry at the physiological pH with the molecular weight close to or even higher than 500 g/mol. 31 − 34 The hydrophobic nature of the ligands implies that their metal complexes could be readily taken up by the cells and localize in lipid dense ER. This suggestion is further supported by our recent findings established by fluorescence microscopy that an indolo[3,2- c ]quinoline-derived ligand EtOOC HL COOEt with inherent fluorescence properties and dizinc(II) complex [Zn 2 ( MeOOC L COO )(OAc) 2 ] were taken by SW480 cells and accumulated in the ER and lysosomes.…”

Developing a Copper(II) Agent Based on His-146 and His-242 Residues of Human Serum Albumin Nanoparticles: Integration To Overcome Cisplatin Resistance and Inhibit the Metastasis of Nonsmall Cell Lung Cancer

“…In the past several decades, because copper (Cu) is an essential metal in the human body and plays a vital role in biological functions, Cu compounds have been extensively studied as the promising next-generation anticancer metal drugs. − Interestingly, many studies have shown that metal compounds can kill cancer cells through multiple mechanisms, − overcome the resistance of cancer cells to cisplatin, and inhibit their metastasis. − Currently, it has been one of the most effectively strategies for the treatment of cancer through acting on the different components of the tumor micro-environment (TME). , Therefore, we may overcome the resistance of NSCLC cells to cisplatin and inhibit their metastasis by rationally designing a new Cu agent that acts on the different components in the TME.…”