TY - JOUR
T1 - Copper(II) Complexes with 2,2′:6′,2″-Terpyridine Derivatives Displaying Dimeric Dichloro−μ-Bridged Crystal Structure
T2 - Biological Activities from 2D and 3D Tumor Spheroids to In Vivo Models
AU - Choroba, Katarzyna
AU - Machura, Barbara
AU - Erfurt, Karol
AU - Casimiro, Ana Rita
AU - Cordeiro, Sandra
AU - Baptista, Pedro V.
AU - Fernandes, Alexandra R.
N1 - Funding Information:
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04378%2F2020/PT#
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04378%2F2020/PT#
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/LA%2FP%2F0140%2F2020/PT#
info:eu-repo/grantAgreement/FCT/OE/2021.08629.BD/PT#
This work was cofinanced by national funds from FCT-Fundação para a Ciência e a Tecnologia, I.P., in the scope of the project UIDP/04378/2020 (doi: 10.54499/UIDP/04378/2020) and UIDB/04378/2020 (doi: 10.54499/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 and doctoral grant 2021.08629.BD (S.C.), and project NANOHEAT (doi: 10.54499/2022.04315.PTDC) and the Research Excellence Initiative of the University of Silesia in Katowice (B.M.). K.C. acknowledges funding from the National Science Center of Poland grant MINIATURA no. 2022/06/X/ST4/00351.
Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/4/11
Y1 - 2024/4/11
N2 - Eight 2,2′:6′,2″-terpyridines, substituted at the 4′-position with aromatic groups featuring variations in π-conjugation, ring size, heteroatoms, and methoxy groups, were employed to enhance the antiproliferative potential of [Cu2Cl2(R-terpy)2](PF6)2. Assessing the cytotoxicity in A2780 (ovarian carcinoma), HCT116 (colorectal carcinoma), and HCT116DoxR (colorectal carcinoma resistant to doxorubicin) and normal primary fibroblasts revealed that Cu(II) complexes with 4-quinolinyl, 4-methoxy-1-naphthyl, 2-furanyl, and 2-pyridynyl substituents showed superior therapeutic potential in HCT116DoxR cells with significantly reduced cytotoxicity in normal fibroblasts (42-129× lower). Besides their cytotoxicity, the Cu(II) complexes are able to increase intracellular ROS and interfere with cell cycle progression, leading to cell death by apoptosis and autophagy. Importantly, they demonstrated antimetastatic and antiangiogenic properties without in vivo toxicity. In accordance with their nuclear accumulation, the Cu(II) complexes are able to cleave pDNA and interact with bovine serum albumin, which is a good indication of their ability for internalization and transport toward tumor cells.
AB - Eight 2,2′:6′,2″-terpyridines, substituted at the 4′-position with aromatic groups featuring variations in π-conjugation, ring size, heteroatoms, and methoxy groups, were employed to enhance the antiproliferative potential of [Cu2Cl2(R-terpy)2](PF6)2. Assessing the cytotoxicity in A2780 (ovarian carcinoma), HCT116 (colorectal carcinoma), and HCT116DoxR (colorectal carcinoma resistant to doxorubicin) and normal primary fibroblasts revealed that Cu(II) complexes with 4-quinolinyl, 4-methoxy-1-naphthyl, 2-furanyl, and 2-pyridynyl substituents showed superior therapeutic potential in HCT116DoxR cells with significantly reduced cytotoxicity in normal fibroblasts (42-129× lower). Besides their cytotoxicity, the Cu(II) complexes are able to increase intracellular ROS and interfere with cell cycle progression, leading to cell death by apoptosis and autophagy. Importantly, they demonstrated antimetastatic and antiangiogenic properties without in vivo toxicity. In accordance with their nuclear accumulation, the Cu(II) complexes are able to cleave pDNA and interact with bovine serum albumin, which is a good indication of their ability for internalization and transport toward tumor cells.
UR - http://www.scopus.com/inward/record.url?scp=85188470878&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.4c00119
DO - 10.1021/acs.jmedchem.4c00119
M3 - Article
C2 - 38518246
AN - SCOPUS:85188470878
SN - 0022-2623
VL - 67
SP - 5813
EP - 5836
JO - Journal Of Medicinal Chemistry
JF - Journal Of Medicinal Chemistry
IS - 7
ER -