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

Rui Rong Ye, Jian Jun Cao, Cai Ping Tan, Liang Nian Ji, Zong Wan Mao

Research output: Contribution to journalArticleResearchpeer-review

47 Citations (Scopus)


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 IrIII complexes have emerged as potential anticancer agents. By conjugation of VPA to IrIII 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.

Original languageEnglish
Pages (from-to)15166-15176
Number of pages11
JournalChemistry - A European Journal
Issue number60
Publication statusPublished - 26 Oct 2017
Externally publishedYes


  • antitumor agents
  • apoptosis
  • imaging agents
  • iridium
  • N ligands

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