A Rhein‐Based Rh(III) Arene Complex with Anti‐tumor Cell Proliferative Activity Inhibits RNA Demethylase FTO

Abstract

Metallodrugs with fine-tuned coordination between metals and bioactive ligands can achieve cytotoxic effects in cancer therapy and have been considered as a new approach for drug design. However, it has yet to be elucidated whether these metallodrugs target epitranscriptomic proteins for gene expression regulation. This report describes a rhein-based Rh(III)-arene complex, Rh1, that exhibited promising antiproliferative effects in several tumor cell lines. Rh1 induced cell death through the autophagy, cell cycle arrest, and accumulation of intracellular reactive oxygen species (ROS). In addition, Rh1 upregulated the global N 6 -methyladenosine (m 6 A) levels in A549 cells in the fat mass-and obesity-associated protein (FTO)-dependent manner. Collectively, the metal-based FTO inhibitor Rh1 effectively suppressed tumor cell proliferation and modulated the abundance of cellular m 6 A, highlighting the potential of metal-based agents to target and regulate epitranscriptomics for tumor suppression.

Chemical Inhibitors Targeting the Oncogenic m6A Modifying Proteins

“…14,22 Additionally, a rhein-based Rh(III)-arene complex inhibiting FTO named Rh1 was reported in 2022. 23 In highlights, CS1 and CS2 are highly potent FTO inhibitors identified in a structure-based virtual screening of 260,000 compounds from the NCI DTP library. 24 Both CS1 and CS2 exhibit significant antitumor effects in mouse models of different cancers such as AML (and relapsed AML), glioblastoma, breast cancer, and pancreatic cancer.…”

“…Entacapone (an FDA-approved drug for Parkinson’s disease), hydrazide-based inhibitor (HZ), and an HZ-MA hybrid represent dual 2OG-substrate competitive FTO inhibitors. There are representative FTO inhibitors whose mode of action have yet to be corroborated as well, including MO-I-500, MU06, CS1/zantrene/bisantrene, and CS2/brequinar (Figure C and Table , “other mechanisms”). , Additionally, a rhein-based Rh­(III)-arene complex inhibiting FTO named Rh1 was reported in 2022 . In highlights, CS1 and CS2 are highly potent FTO inhibitors identified in a structure-based virtual screening of 260,000 compounds from the NCI DTP library .…”

Copper‐Free Click Chemistry‐Mediated Assembly of Single Quantum Dot Nanosensor for Accurately Monitoring Locus‐Specific m6A in Cancer Cells†

“…[ 6 ] The level of m 6 A is reversibly controlled by RNA methyltransferases ( e.g ., methyltransferase‐like 16 (METTL16), METTL3 and METTL14) and RNA demethylase ( e.g ., fat mass and obesity‐associated protein (FTO)). [ 7‐10 ] Consequently, the construction of sensitive methods for quantitative detection of m 6 A is highly required. [ 11 ]…”

N^N^C-Cyclometalated rhodium(iii) complexes with isomeric pyrimidine-based ligands: unveiling the impact of isomerism on structural motifs, luminescence and cytotoxicity

“…Our particular interest to rhodium complexes stems partly from our experience in rhodium chemistry 82–84 and partly from appealing properties this metal shows in the C–H bond activation and catalysis, 85–91 photochemistry 92–107 and bioinorganic chemistry. 108–128 Along with the synthesis of HL 2,5 and HL 2,6 and their rhodium( iii ) complexes [RhL 2,5 (Solv)Cl 2 ]· n EtOH and [RhL 2,6 (Solv)Cl 2 ]· n EtOH , here we report the impact of isomerism on molecular and supramolecular structures of these compounds, on the photophysical properties of the rhodium( iii ) complexes and on the cytotoxic activity of the ligands and complexes. These experimental studies are supplemented by the theoretical investigation of photophysical properties of the complexes and by theoretical modelling of the sp 2 C–H bond activation which occurs upon the coordination of HL 2,5 and HL 2,6 to RhCl 3 .…”