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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents
Published on: May 28, 2014
Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on
M Isabel Acuña1, Ana R Rubio2,3, Marta Martínez-Alonso2
1CIMUS, Universidad de Santiago de Compostela, Avenida Barcelona s/n, 15782 Santiago de Compostela, Spain.
Abstract:
Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability.
Insights
This study introduces a novel iridium complex, 1[C,NH-Cl], that selectively targets cancer cell mitochondria. This compound disrupts mitochondrial function, induces cell death, and reduces tumor growth in mice, offering a promising new cancer treatment strategy.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Mitochondrial Biology
Background:
- Cancers develop resistance to targeted therapies by accumulating genetic mutations.
- Mitochondria are crucial for tumor progression and represent a potential therapeutic target.
- Iridium complexes show anticancer activity but often lack specificity, causing side effects.
Purpose of the Study:
- To systematically investigate structure-activity relationships of arylbenzazole-based Iridium(III) complexes.
- To identify an iridium complex with high specificity for cancer cells and minimal side effects.
- To elucidate the mechanism of action of the most promising complex.
Main Methods:
- Synthesis and characterization of eight [IrCl(Cp*)]-type iridium(III) complexes.
- Evaluation of structure-activity relationships, including physical chemistry properties and cytotoxicity.
- Assessment of DNA and albumin binding, mitochondrial targeting, membrane permeability, ROS generation, and cell death induction.
- In vivo studies using mice with orthotopic lung tumors.
Main Results:
- Complex 1[C,NH-Cl], a neutral phenylbenzimidazole-based iridium(III) complex, showed high selectivity.
- This complex selectively targeted mitochondria, disturbed mitochondrial membrane permeability, increased ROS levels, and triggered regulated cell death.
- Complex 1[C,NH-Cl] did not bind to DNA or albumin.
- Administration of complex 1[C,NH-Cl] reduced tumor burden in mice with orthotopic lung tumors.
Conclusions:
- Complex 1[C,NH-Cl] effectively targets cancer cell mitochondria, inducing cell death and reducing tumor growth.
- This compound offers a new strategy to exploit cancer's vulnerability to mitochondrial dysfunction.
- Further development of complex 1[C,NH-Cl] could lead to novel anticancer therapeutics.
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