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高度抗增殖的拉顿丁和吲[2,3-]喹啉衍生物：与铜（II）形成配合物显著改变激酶抑制特性。

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

机构信息

Institute of Inorganic Chemistry of the University of Vienna, Währinger Strasse, 42, Vienna A1090, Austria.

Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, Szeged H-6720, Hungary.

出版信息

J Med Chem. 2022 Feb 10;65(3):2238-2261. doi: 10.1021/acs.jmedchem.1c01740. Epub 2022 Feb 1.

DOI:10.1021/acs.jmedchem.1c01740
PMID:35104137
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8842277/
Abstract

A series of latonduine and indoloquinoline derivatives - and their copper(II) complexes () were synthesized and comprehensively characterized. The structures of five compounds (, , , , and ) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC 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 and as well as and induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. showed selective inhibition for the PIM-1 enzyme, while 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.

摘要

一系列拉顿杜因和吲哚喹啉衍生物及其铜(II)配合物()被合成并进行了全面的表征。通过单晶 X 射线衍射确定了五个化合物（、、、、和）的结构。与多柔比星敏感的 Colo205 细胞系相比，铜(II)配合物对人结肠腺癌多药耐药 Colo320 癌细胞具有低至亚微摩尔的 IC 值，且具有良好的选择性。先导化合物和以及和能够有效地诱导 Colo320 细胞凋亡。此外，铜(II)配合物与 DNA 的亲和力高于其游离配体。显示出对 PIM-1 酶的选择性抑制，而则对 50 种激酶中的其他 5 种酶，即 SGK-1、PKA、CaMK-1、GSK3β 和 MSK1，具有强烈的抑制作用。此外，配体和配合物的分子建模表明它们与这些靶标的结合口袋具有良好的契合度。

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