Photoactivation of Boronic Acid Prodrugs via a Phenyl Radical Mechanism: Iridium(III) Anticancer Complex as an Example

Moyi Liu, Yunli Luo, Junyu Yan, Xiaolin Xiong, Xiwen Xing, Jong Seung Kim, Taotao Zou

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Boronic acid (or ester) is a well-known temporary masking group for developing anticancer prodrugs responsive to tumoral reactive oxygen species (ROS), but their clinic application is largely hampered by the low activation efficiency. Herein, we report a robust photoactivation approach that can spatiotemporally convert boronic acid-caged iridium(III) complex IrBA into bioactive IrNH2 under hypoxic tumor microenvironments. Mechanistic studies show that the phenyl boronic acid moiety in IrBA is in equilibrium with phenyl boronate anion that can be photo-oxidized to generate phenyl radical, a highly reactive species that is capable of rapidly capturing O2 at extremely low concentrations (down to 0.02%). As a result, while IrBA could hardly be activated by intrinsic ROS in cancer cells, upon light irradiation, the prodrug is efficiently converted into IrNH2 even in limited O2 supply, along with direct damage to mitochondrial DNA and potent antitumor activities in hypoxic 2D monolayer cells, 3D tumor spheroids, and mice bearing tumor xenografts. Of note, the photoactivation approach could be extended to intermolecular photocatalytic activation by external photosensitizers with red absorption and to activate prodrugs of clinic compounds, thus offering a general approach for activation of anticancer organoboron prodrugs.

Original languageEnglish
Pages (from-to)10082-10091
Number of pages10
JournalJournal of the American Chemical Society
Volume145
Issue number18
DOIs
Publication statusPublished - 2023 May 10

Bibliographical note

Funding Information:
This work was financially supported by National Natural Science Foundation of China (No. 22122706), Guangdong Science and Technology Department (No. 2019QN01C125), Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515012347), Guangzhou Science and Technology Projects (No. 202102020790), Guangdong Provincial Key Lab of Chiral Molecule and Drug Discovery (No. 2019B030301005), Key Laboratory of Bioinorganic and Synthetic Chemistry of Ministry of Education (Sun Yat-Sen University), National Key R&D Program of China (2022YFC2804101), and Outstanding Youth Project of Guangdong Natural Science Foundation (2022B1515020047).

Publisher Copyright:
© 2023 American Chemical Society

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry

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