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

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

Chemistry. 2017 Aug 22;:

Authors: Ye RR, Cao JJ, Tan CP, Ji LN, Mao ZW

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(III) complexes have emerged as potential anticancer agents. Conjugation of VPA to Ir(III) complexes by ester bond, we designed and synthesized three VPA-functionalized cyclometalated iridium(III) complexes (1a-3a). These complexes display excellent two-photon properties, which is favorable for live cell imaging. The ester bonds in 1a-3a can be hydrolysed quickly by esterase, and display similar inhibition on the HDAC activity to VPA. Notably, 1a-3a can overcome cisplatin resistance effectively, about 54.5-89.7 times more cytotoxic than cisplatin against cisplatin-resistant human lung carcinoma (A549R) cells. Mechanism 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. Our study gives insights into the design and anticancer mechanisms of multifunctional anticancer agents.

PMID: 28833658 [PubMed - as supplied by publisher]

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