Anticancer Cyclometalated Iridium(III) Complexes with Planar Ligands: Mitochondrial DNA Damage and Metabolism Disturbance

Journal of Medicinal Chemistry
Jian-Jun CaoZong-Wan Mao

Abstract

Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity than cisplatin and they can effectively localize to mitochondria. Among them, complexes Ir3 and Ir4 with dipyrido[3,2- a:2',3'- c]phenazine (dppz) ligands can bind to DNA tightly in vitro, intercalate to mtDNA in situ, and induce mtDNA damage. Ir3- and Ir4-impaired mitochondria exhibit decline of mitochondrial membrane potential, disability of adenosine triphosphate generation, disruption of mitochondrial energetic and metabolic status, which subsequently cause protective mitophagy, G0/G1 phase cell cycle arrest, and apoptosis. In vivo antitumor evaluations also show that Ir4 can inhibit tumor xenograft growth effectively. Overall, our work proves that targeting the mitochondrial genome may present an effective strategy to develop metal-based anticancer agents to overcome cisplatin resistance.

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Citations

Jul 11, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·Taj-Malook KhanZhen-Feng Chen
Apr 2, 2020·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Yi LiZong-Wan Mao
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May 15, 2021·Journal of Inorganic Biochemistry·Jing HaoDegang Xing
Jun 12, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Yan-Bo PengPing Zhao
Aug 4, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Utpal DasPriyankar Paira
Mar 26, 2020·Journal of Medicinal Chemistry·Ana Cristina CarrascoAna M Pizarro
Aug 28, 2021·Journal of Inorganic Biochemistry·Yan-Bo PengPing Zhao
Nov 4, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Yan YangHong Liang
Nov 13, 2021·Inorganic Chemistry·Rajeeva Lochana PanchangamKaushik Chanda

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