Platinum(II) Terpyridine Anticancer Complexes Possessing Multiple Mode of DNA Interaction and EGFR Inhibiting Activity

Abstract

Platinum(II) terpyridine complexes has attracted increasing attention as they have displayed great potential as antitumor agents due to their high intercalation affinity with nucleic acids. Epidermal growth factor receptor (EGFR) is often overexpressed in various tumor cells, leading to uncontrolled growth of tumor, and is regarded as an important target for developing novel antitumor drugs. Herein, we report four platinum(II) terpyridine complexes bearing EGFR inhibiting 4-anilinoquinazoline derivatives as potent multi-targeting antiproliferation agents against a series of cancer cells. EGFR inhibition assay revealed that these complexes are highly potent EGFR inhibitors. But competitive DNA binding assay and docking simulations also suggested that these complexes exhibited multiple modes of DNA interaction, especially great affinity toward DNA minor groove. Finally, cellular uptake and distribution measurements by inductively coupled plasma mass spectrometry (ICP-MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) demonstrated that both nucleus DNA and membrane proteins are important targets for their anticancer mechanisms. The complexes herein can therefore be regarded as promising multi-targeting anticancer agents.

Design, Synthesis, and Cytotoxicity Assessment of [64Cu]Cu-NOTA-Terpyridine Platinum Conjugate: A Novel Chemoradiotherapeutic Agent with Flexible Linker

“…This finding is consistent with previous observations showing about a five-fold lower cellular uptake of another platinum (II)-terpyridine complex in the same GM05757 fibroblasts relative to human cancer cells [ 34 ]. Note that the epidermal growth factor receptor (EGFR), which is often overexpressed in cancer cells, has been recently reported as a potential target for platinum (II)-terpyridine compounds [ 40 ]. This molecular pathway could be a possible mechanism for higher internalization as well as the subcellular accumulation of [ 64 Cu]Cu-NOTA-C3-TP in HCT116 cancer cells.…”

Single cell imaging reveals cisplatin regulating interactions between transcription (co)factors and DNA

“…It should be noted that for single cell imaging, platinum-containing species generally produce recombinant ions [PtCN] À and [PtC 2 N 2 ] À , in negative ToF-SIMS analysis. [29][30][31] Herein, only [PtCN] À was used to image the platinumcontaining species throughout this work as it displayed the characteristic isotopic pattern and good signal-to-noise ratio, and its signal intensity was closely related to the concentration of cisplatin in cells (vide infra). It is worthy to point out that the ToF-SIMS image did not show the localization of cisplatin in the cytoplasm region 32 as GCIB sputtering may have removed most of cytoplasm layer prior to SIMS imaging ( Fig.…”

Di-μ-chlorido-bis[(2,2′:6′,2′′-terpyridine-κ3 N,N′,N′′)copper(II)] bis(trifluoromethanesulfonate)

“…Terpyridines are some of the most studied nitrogen-based tridentate ligands in coordination chemistry, and their metal complexes have found application in catalysis (Wei et al, 2019;Choroba et al, 2019), supramolecular chemistry (Wei et al, 2019), and medicinal chemistry (Glis ˇic ´et al, 2018;Malarz et al, 2021;Li et al, 2020). Recently, copper(II) terpyridine complexes have received much attention due to their remarkable cytotoxicity and ability to interact with DNA (Karges et al, 2021); herein, we report the synthesis and structure of the title copper(II) terpyridine complex.…”