Selectively and efficiently eliciting a ROS-dependent energy crisis within cancer cells through a mitochondria-targeted catechol-based diphenylhextriene

  • Bioorg Chem. 2026 Mar:170:109505. doi: 10.1016/j.bioorg.2026.109505.
Xia-Zhen Bao  1 ,  Xiao-Rong Ren  2 ,  Wei Tang  3 ,  Yu Zhang  3 ,  Zheng-Kai Deng  3 ,  Fang Dai  4 ,  Bo Zhou  5
Affiliations
  • 1. State Key Laboratory of Natural Product Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China; College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China.
  • 2. State Key Laboratory of Natural Product Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China; School of Chemistry and Chemical Engineering, Shaoxing University, 1077 Chengnan Avenue, Shaoxing, Zhejiang 312000, China.
  • 3. State Key Laboratory of Natural Product Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
  • 4. State Key Laboratory of Natural Product Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Natural Product Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China. Electronic address: [email protected].
PMID: 41547039 DOI: 10.1016/j.bioorg.2026.109505
Abstract

To effectively trigger an energy crisis within Cancer cells, we devised and synthesized mitochondria-targeted catechol-based diphenylpolyenes by coupling them with a triphenylphosphonium unit via a modular synthetic approach. The exploration of structure-activity relationships in terms of cytotoxicity discloses that Mito-DHH, a catechol-type diphenylhextriene that specifically targets mitochondria, is the most potent molecule among those tested, manifesting its preferential elimination of A549 cells (IC50 = 0.25 μM) as opposed to normal L02 cells (IC50 = 2.8 μM). In this regard, it outperforms doxorubicin and 5-fluorouracil, the commonly employed chemotherapy drugs. Mechanistic investigation affirms that the rapid accumulation of Mito-DHH within mitochondria of A549 cells enables its efficient auto-oxidation by leveraging the alkaline mitochondrial matrix to effectively and selectively generate Reactive Oxygen Species (ROS). Through the generation of ROS, Mito-DHH initiates a ROS-dependent reduction of ATP levels within A549 cells in a dual-effect inhibitory pattern against both mitochondrial and glycolytic metabolisms, and the ultimate and selective Apoptosis of A549 cells. This study takes Mito-DHH as an example to emphasize the universality of a ROS-generating strategy by targeting mitochondria in effectively inducing an energy crisis within Cancer cells.

Keywords
Apoptosis; Catechol; Energy crisis; Metabolic reprograming; Mitochondria; Reactive oxygen species.
Products