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

Abstract

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 complexes have emerged as potential anticancer agents. By conjugation of VPA to Ir complexes through an ester bond, VPA-functionalized cyclometalated iridium(III) complexes 1 a-3 a were designed and synthesized. These complexes display excellent two-photon properties, which are favorable for live-cell imaging. The ester bonds in 1 a-3 a can be hydrolyzed quickly by esterase and display similar inhibition of HDAC activity to VPA. Notably, 1 a-3 a 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 1 a-3 a 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.

Unprecedented collateral sensitivity for cisplatin-resistant lung cancer cells presented by new ruthenium organometallic compounds

“…One of the strategies used has been the codelivery of valproic acid (VPA), a histone deacetylase inhibitor, with a metallodrug. 13,14 For example, Mao and co-workers have developed VPA-functionalized cyclometalated iridium(III) complexes through a hydrolysable ester bond. 13 The results have shown a significant increased activity for the new conjugates (vs. VPA alone or a mixture of complexes + VPA) validating the strategy adopted.…”

“…13,14 For example, Mao and co-workers have developed VPA-functionalized cyclometalated iridium(III) complexes through a hydrolysable ester bond. 13 The results have shown a significant increased activity for the new conjugates (vs. VPA alone or a mixture of complexes + VPA) validating the strategy adopted. Also, the conjugates were able to overcome cisplatin resistance in human lung carcinoma cells (A549R).…”

GANT61 and Valproic Acid Synergistically Inhibited Multiple Myeloma Cell Proliferation via Hedgehog Signaling Pathway

“…Among them, valproic acid (VPA) is a well-established anti-convulsant drug and has been safely applied for 3 decades [17]. The bioavailability of these oral dosage forms approaches 95% to 100% and is well tolerated by patients [3,18,19]. In recent years, VPA was also suggested to exert its anti-cancer effects by suppressing histone deacetylase [20].…”

Iridium(III) Complexes Targeting Apoptotic Cell Death in Cancer Cells

“…This has driven the search for other metal-based anticancer agents that retain the potency of the platinum drugs but possess fewer side effects. To date, a variety of non-platinum transition metal-based complexes, including osmium, gold, ruthenium, rhodium, and palladium complexes, have been intensively exploited for their potential use as anticancer drugs [4,5,6,7,8,9,10,11].…”