Citation:

Optimization of Antiproliferative Properties of Triimine Copper(II) Complexes, Choroba, Katarzyna, Zowiślok Bartosz, Kula Sławomir, Machura Barbara, Maroń {Anna M. }, Erfurt Karol, Marques Cristiana, Cordeiro Sandra, Baptista {Pedro V. }, and Fernandes {Alexandra R. } , Journal Of Medicinal Chemistry, Volume 67, Number 21, p.19475–19502, (2024)

Abstract:

Cu(II) complexes with 2,2′:6′,2″-terpyridines (terpy) and 2,6-bis(thiazol-2-yl)pyridines (dtpy) with 1- or 2-naphtyl and methoxy-naphtyl were synthesized to elucidate the impact of the triimine core, naphtyl linking mode, and presence of methoxy groups on the antiproliferative activity of [CuCl2(Ln)]. Their antiproliferative effect was analyzed in ovarian (A2780) and colorectal (HCT116) carcinomas and colorectal carcinoma resistant to doxorubicin (HCT116-DoxR) cell lines and in normal human fibroblasts. Among all complexes, the 1- and 2-naphtyl substituted terpy Cu(II) complexes (Cu1a and Cu1b) showed the strongest cytotoxicity, namely, in HCT116-DoxR 2Dcells and were also capable of inducing the loss of cell viability in 3D HCT116-DoxR spheroids. Their intracellular localization, capability to increase reactive oxygen species (ROS), and interaction with DNA (nonintercalative mode) trigger oxidative DNA cleavage leading to cell death by apoptosis and autophagy. Cu1a and Cu1b do not show in vivo toxicity in a chicken embryo and can interact with bovine serum albumin (BSA).

Notes:

Funding Information: This research was funded by the National Science Centre of Poland, SONATA grant no. 2020/39/D/ST4/00286 (A.M.M.). The research activities were cofinanced by the funds granted under the Research Excellence Initiative of the University of Silesia in Katowice. This work was also financed by national funds from FCT - Fundac\u0327a\u0303o para a Cie\u0302ncia e a Tecnologia, I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences - UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy - i4HB. We also thank Fundac\u0327a\u0303o para a Cie\u0302ncia e Tecnologia (FCT), I.P./MCTES for the financial support through the project NANOHEAT (DOI: 10.54499/2022.04315.PTDC). S.C. was funded by FCT/MCTES, grant number 2021.08629.BD. Publisher Copyright: © 2024 The Authors. Published by American Chemical Society.