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Published on: May 28, 2014
Naphthoyl benzhydrazine-decorated binuclear arene Ru(II) complexes as anticancer agents targeting human breast cancer
Arunachalam Abirami1, Umapathy Devan2, Rengan Ramesh1
1Centre for Organometallic Chemistry, School of Chemistry, Bharathidasan University, Tiruchirappalli - 620 024, India. rramesh@bdu.ac.in.
Abstract:
Breast cancer is the most dangerous type in women and its fatality rate has increased over the past decade. To develop more potent and target-specific breast cancer drugs, six arene ruthenium(II) complexes (1-6) containing naphthoyl benzhydrazine ligands (NL1-NL3) were synthesized and characterized by analytical and spectroscopic (infrared, UV-visible, NMR and HR-MS) methods. The SC-XRD analysis of 1 and 6 demonstrates the bis N^O bidentate binding nature of ligands to ruthenium ions and a pseudo-octahedral geometry around the Ru(II) ion. Solution stability studies using UV-Vis spectroscopy evidenced the instantaneous hydrolysis of the complexes to form monoaquated species in a solution of 1 : 9 (v/v) DMSO/phosphate buffer. All the complexes were screened for their in vitro antiproliferative activities against different human breast cancer cells, including MCF-7, SkBr3, MDA-MB-468, MDA-MB-231, and non-cancerous HEK-293 cells, by an MTT assay, and they displayed good cancer cell growth inhibitory capacity with low IC50 values. Notably, complexes 2 and 5 comprising methoxy and p-cymene groups exhibited excellent cytotoxicity towards SkBr3 cells compared to clinical drug cisplatin. AO-EB and HOECHST-33342 staining assays revealed apoptotic morphological changes in complex-treated cancer cells. Further, reactive oxygen species and mitochondrial membrane potential assays validated that the complexes induce apoptotic cell death via an intrinsic mitochondrial pathway with ROS production. In addition, the apoptotic induction and the quantification of late apoptosis were established with the aid of western blot and flow cytometry analysis, respectively.
Insights
New ruthenium(II) complexes show potent antiproliferative activity against breast cancer cells. Complexes 2 and 5 demonstrated significant cytotoxicity, inducing apoptosis via the mitochondrial pathway.
Area of Science:
- Inorganic Chemistry
- Medicinal Chemistry
- Cancer Biology
Background:
- Breast cancer poses a significant threat to women's health, with increasing fatality rates.
- There is a critical need for novel, targeted therapeutic agents to combat drug-resistant breast cancer.
- Ruthenium complexes are being explored for their potential anticancer properties.
Purpose of the Study:
- To synthesize and characterize novel arene ruthenium(II) complexes with naphthoyl benzhydrazine ligands.
- To evaluate the in vitro antiproliferative activity of these complexes against various human breast cancer cell lines.
- To elucidate the mechanism of action, including apoptosis induction and the role of mitochondrial pathways.
Main Methods:
- Synthesis and characterization of six arene ruthenium(II) complexes using spectroscopic and analytical techniques.
- In vitro antiproliferative assays (MTT) against MCF-7, SkBr3, MDA-MB-468, and MDA-MB-231 cell lines.
- Apoptosis assays (AO-EB, HOECHST-33342 staining, ROS, mitochondrial membrane potential, Western blot, flow cytometry).
Main Results:
- Complexes 1-6 were successfully synthesized and characterized, with SC-XRD confirming pseudo-octahedral geometry.
- All complexes exhibited significant antiproliferative activity, with low IC50 values against tested cancer cells.
- Complexes 2 and 5 showed superior cytotoxicity compared to cisplatin, particularly against SkBr3 cells.
- Apoptosis was induced through the intrinsic mitochondrial pathway, involving reactive oxygen species (ROS) production.
Conclusions:
- The synthesized arene ruthenium(II) complexes possess promising anticancer potential.
- Complexes 2 and 5 are particularly effective against specific breast cancer subtypes, warranting further investigation.
- The mechanism of action involves ROS generation and intrinsic mitochondrial apoptosis induction.
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