Mitochondria-Targeting Click-Derived Pyridinyltriazolylmethylquinoxaline-Based Y-Shaped Binuclear Luminescent Ruthenium(II) and Iridium(III) Complexes as Cancer Theranostic Agents

Abstract

Due to several negative issues, market available drugs have been gradually losing their importance in the treatment of cancer. With a view to discover suitable drugs capable of diagnosing as well as inhibiting the growth of cancer cells, we have aspired to develop a group of theranostic metal complexes which will be (i) target specific, (ii) cytoselective, thus rendering the normal cell unaffected, (iii) water-soluble, (iv) cancer cell permeable, and (v) luminescent, being beneficial for healing the cancer eternally. Therefore, to reach our goal, we have prepared novel Ru­(II)- and Ir­(III)-based bimetallic and hetero bimetallic scaffolds using click-derived pyridinyltriazolylmethylquinoxaline ligands followed by metal coordination. Most of the compounds have displayed significant cytoselectivity against colorectal adenocarcinoma (Caco-2) and epithiloid cervical carcinoma (HeLa) cells with respect to normal human embryonic kidney cells (HEK-293) compared to cisplatin [cis-diamminedichloroplatinum­(II)] along with excellent binding efficacy with DNA as well as serum albumin. Complex [(η6-p-cymene)­(η5-Cp*)­RuIIIrIIICl2(K2-N,N-L)]­(PF6)2 [RuIrL] exhibited the best cytoselectivity against all the human cancer cells and was identified as the most significant cancer theranostic agent in terms of potency, selectivity, and fluorescence quantum yield. Investigation of the localization of complex [Ir 2 L] and [RuIrL] in the more aggressive colorectal adenocarcinoma cell HT-29 indicates that mitochondria are the key cellular target for destroying cancer cells. Mitochondrial dysfunction and G2/M phase cell cycle arrest in HT-29 cell were found to be involved in the apoptotic cell death pathway induced by the test complexes [Ir 2 L] and [RuIrL]. These results validate the concept that these types of complexes will be reasonably able to exert great potential for tumor diagnosis as well as therapy in the near future.

Expanding the Limits of Photodynamic Therapy: The Design of Organelles and Hypoxia-Targeting Nanomaterials for Enhanced Photokilling of Cancer

“…The positive charge is relocated on a portion of their structures, which, along with their lipophilic-favored nature, can easily cross phospholipid bilayers . Some of the most commons DLCs used in PDT are triphenyl­phosphonium (TPP) monocation derivatives as well as metal–organic Iridium­(III) and Ruthenium­(II) complexes …”

“…121 Some of the most commons DLCs used in PDT are triphenylphosphonium (TPP) monocation derivatives as well as metal−organic Iridium(III) and Ruthenium(II) complexes. 122 Encouraged by their effects of charge, a series of other compounds have presented significant accumulation in mitochondria that include inner salt-shaped organic photosensitizers 123 and a number of carbon-based NPs such as carbon nanotubes and graphene oxide. 124,125 Additionally, mitochondria-targeting peptides are currently in development.…”

Mitochondria-targeted half-sandwich iridium(iii)-Cp*-arylimidazophenanthroline complexes as antiproliferative and bioimaging agents against triple negative breast cancer cells MDA-MB-468

“…1). [13][14][15][16][17][18] and evaluated their antiproliferative activity against MDA-MB-468 TNBC cells that are EGFR +ve, TGF alpha +ve, high in Ki67. These complexes exhibited dual properties like (i) killing of cancer cells via DNA damage (ii) mitochondrial dysfunction by ROS production.…”

Antitumor Effect of Organometallic Half-Sandwich Ru(II)–Arene Complexes Bearing a Glutathione S-Transferase Inhibitor

“…In addition, the inevitable drug resistance is another limitation of the platinum drugs . Considering the disadvantages of platinum drugs, other metal-based anticancer compounds have been designed as alternatives to platinum drugs, especially ruthenium-based anticancer agents, which has shown great promising in cancer therapy due to their unique biological properties and low toxicity. − …”

“…In Vitro Cytotoxic Activity. The cytotoxic activities of ligand L1 and complexes 1−3 against MCF-7 (breast cancer), A549 (nonsmall cell lung cancer), and normal liver cell line LO2 were evaluated by an MTT assay together with [(η 6 -pcymene)Ru(1,10-phenanthroline-κN 1 ,κN 10 )Cl]Cl (abbreviated as Ru-con) and cisplatin as positive control after 72 h incubation. After three parallel experiments, the IC 50 values (the dose required to inhibit 50% cell growth) were determined according to the dose-survival curve (Table 1).…”