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New water-soluble palladium(II) complexes of lidocaine and phenylcyanamide derivative ligands: cytotoxicity and cellular response mechanisms

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Summary

Three new palladium(II) complexes of lidocaine and phenylcyanamide derivative ligands of formula K[Pd(2,6-Me2pcyd)2(LC)], 1, K[Pd(2,6-Et2pcyd)2(LC)], 2, K[Pd(2,6-Cl2pcyd)2(LC)], 3 (LC: lidocaine, 2,6-Me2pcyd: 2,6-dimethyl phenylcyanamide, 2,6-Et2pcyd: 2,6-diethyl phenylcyanamide, 2,6-Cl2pcyd: 2,6-dichloro phenylcyanamide) have been synthesized and fully characterized. The complexes 1–3 revealed a significant in vitro antiproliferative activity against human ovarian carcinoma (A2780), colorectal adenocarcinoma (HT29), breast (MCF-7), liver hepatocellular carcinoma (HepG-2) and lung adenocarcinoma (A549) cancer cell lines. All the complexes are more active than cisplatin and follow the trend 2 > 1 > 3. Mechanistic studies showed that the trend in cytotoxicity of the Pd(II) complexes is mainly consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which consequently results in the loss of mitochondrial membrane potential and apoptosis induction.

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Abbreviations

LC:

Lidocaine

2,6-Me2pcyd:

2,6-dimethyl phenylcyanamide

2,6-Et2pcyd:

2,6-diethyl phenylcyanamide

2,6-Cl2pcyd:

2,6-dichloro phenylcyanamide

DMSO:

Dimethyl sulfoxide

ROS:

Reactive oxygen species

SRA:

Steroid resistant asthma

PBS:

Phosphate-buffered saline

CM-H2DCFDA:

5-(and-6)-chloromethyl-2′,7′- dichlorodihydrofluorescein diacetate acetyl ester

TMRM:

Tetramethyl rhodamine methyl ester

MTT:

3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyl tetrazolium bromide

AMC:

7-amino-4-methylcoumarin

MMP:

Mitochondrial membrane potential

IC50 :

Half maximal inhibitory concentration

DMEM:

Dulbecco’s Modified Eagle Medium

FT-IR:

Fourier transform infrared spectroscopy

NMR:

Nuclear magnetic resonance

HPLC:

High Performance Liquid Chromatography

GFAAS:

Graphite furnace atomic absorption spectroscopy

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Acknowledgments

We acknowledge general support from the Department of Chemistry, Isfahan University of Technology (IUT).

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Authors and Affiliations

  1. Department of Chemistry, Isfahan University of Technology, Isfahan, 84156-83111, Iran

    Leila Tabrizi & Hossein Chiniforoshan

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  1. Leila Tabrizi
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Correspondence to Leila Tabrizi or Hossein Chiniforoshan.

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The authors, Leila Tabrizi and Hossein Chiniforoshan, declare that they have no conflict of interest.

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The work was supported by the Department of Chemistry, Isfahan University of Technology in Isfahan-Iran.

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Tabrizi, L., Chiniforoshan, H. New water-soluble palladium(II) complexes of lidocaine and phenylcyanamide derivative ligands: cytotoxicity and cellular response mechanisms. Invest New Drugs 34, 723–732 (2016). https://doi.org/10.1007/s10637-016-0393-0

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