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Valproic Acid‐Functionalized Cyclometalated Iridium(III) Complexes as Mitochondria‐Targeting Anticancer Agents
Author(s) -
Ye RuiRong,
Cao JianJun,
Tan CaiPing,
Ji LiangNian,
Mao ZongWan
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201703157
Subject(s) - cisplatin , hela , chemistry , mitochondrion , apoptosis , cancer cell , cytotoxicity , histone deacetylase inhibitor , iridium , histone deacetylase , biochemistry , in vitro , cancer research , cancer , histone , biology , genetics , chemotherapy , gene , catalysis
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 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.