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

Valproic acid (VPA) is a short-chain, fatty acid type histone deacetylase inhibitor (HDACi), which can cause growth arrest and induce differentiation of transformed cells. Phosphorescent cyclometalated Ir-III complexes have emerged as potential anticancer agents. By conjugation of VPA to Ir-III complexes through an ester bond, VPA-functionalized cyclometalated iridium(III) complexes 1a-3a were designed and synthesized. These complexes display excellent two-photon properties, which are favorable for live-cell imaging. The ester bonds in 1a-3a can be hydrolyzed quickly by esterase and display similar inhibition of HDAC activity to VPA. Notably, 1a-3a can overcome cisplatin resistance effectively and are about 54.5-89.7 times more cytotoxic than cisplatin against cisplatin-resistant human lung carcinoma (A549R) cells. Mechanistic studies indicate that 1a-3a can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, accumulate in mitochondria, and induce a series of cell-death-related events mediated by mitochondria. This study gives insights into the design and anticancer mechanisms of multifunctional anticancer agents.