Mitochondria-Selective Dicationic Small-Molecule Ligand Targeting G‑Quadruplex Structures for Human Colorectal Cancer Therapy

• Published in: Journal of medicinal chemistry 2024-04, Vol.67 (8), p.6292-6312
• Main Authors: Zheng, Bo-Xin, Long, Wei, Zheng, Wende, Zeng, Yaoxun, Guo, Xiao-Chun, Chan, Ka-Hin, She, Meng-Ting, Leung, Alan Siu-Lun, Lu, Yu-Jing, Wong, Wing-Leung
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; DNA, Mitochondrial - metabolism; G-Quadruplexes - drug effects; HCT116 Cells; Humans; Ligands; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Nude; Mitochondria - drug effects; Mitochondria - metabolism; Reactive Oxygen Species - metabolism; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c02240

Mitochondria are important drug targets for anticancer and other disease therapies. Certain human mitochondrial DNA sequences capable of forming G-quadruplex structures (G4s) are emerging drug targets of small molecules. Despite some mitochondria-selective ligands being reported for drug delivery against cancers, the ligand design is mostly limited to the triphenylphosphonium scaffold. The ligand designed with lipophilic small-sized scaffolds bearing multipositive charges targeting the unique feature of high mitochondrial membrane potential (MMP) is lacking and most mitochondria-selective ligands are not G4-targeting. Herein, we report a new small-sized dicationic lipophilic ligand to target MMP and mitochondrial DNA G4s to enhance drug delivery for anticancer. The ligand showed marked alteration of mitochondrial gene expression and substantial induction of ROS production, mitochondrial dysfunction, DNA damage, cellular senescence, and apoptosis. The ligand also exhibited high anticancer activity against HCT116 cancer cells (IC50, 3.4 μM) and high antitumor efficacy in the HCT116 tumor xenograft mouse model (∼70% tumor weight reduction).