Valproic Acid-Functionalized Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents

Area of Science:

• Medicinal Chemistry
• Nanotechnology
• Biochemistry

Background:

• Valproic acid (VPA) is a histone deacetylase inhibitor (HDACi) with anticancer properties.
• Cyclometalated Iridium(III) complexes are promising anticancer agents with phosphorescent properties.

Purpose of the Study:

• To design and synthesize VPA-functionalized iridium(III) complexes for enhanced anticancer therapy.
• To investigate the anticancer efficacy, mechanism of action, and imaging capabilities of these novel complexes.

Main Methods:

• Synthesis of VPA-conjugated cyclometalated iridium(III) complexes (1a-3a).
• Evaluation of two-photon properties for live-cell imaging.
• Assessment of HDAC inhibition and cytotoxicity against cisplatin-resistant cancer cells.
• Mechanistic studies involving cellular uptake, mitochondrial accumulation, and induction of cell death.

Main Results:

• The synthesized complexes (1a-3a) exhibit excellent two-photon properties.
• Ester bonds in 1a-3a are rapidly hydrolyzed by esterase, restoring HDAC inhibition similar to VPA.
• Complexes 1a-3a demonstrate significant cytotoxicity against cisplatin-resistant lung carcinoma cells (A549R), exceeding cisplatin by 54.5-89.7 times.
• Cellular studies show rapid uptake, mitochondrial accumulation, and induction of mitochondrial-mediated cell death in HeLa cells.

Conclusions:

• VPA-functionalized iridium(III) complexes represent a novel class of multifunctional anticancer agents.
• These complexes possess potent anticancer activity, overcome cisplatin resistance, and induce cell death via mitochondrial pathways.
• The designed complexes offer potential for targeted cancer therapy and advanced bioimaging applications.