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The Cytotoxicity Profile, Apoptosis Mechanism, and Molecular Docking Studies of a Series of Benzimidazolium Derivative Morpholine-Substituted Ag(I) Heterocyclic Carbene Complexes

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Pharmaceutical Chemistry Journal Aims and scope

The main problems experienced in treatment with anticancer drugs are undesirable side effects, and toxicity. Minimal side effects for new anticancer compounds may be met due to enhanced efforts to clarify the compound’s mechanisms of action. Therefore, we aimed to investigate whether or the cytotoxic effect and apoptosis mechanism of a series Ag(I)NHC complexes on non-small cell lung cancer cell line (A549) and normal lung fibroblast cell line (CCD-19Lu) in this study. The cytotoxicity was determined by using the MTT method, and apoptotic effects were detected by cell cycle, annexin-V/propidium iodide (PI) staining and cell cycle, caspase-3, mitochondrial membrane potential analysis. Molecular docking studies were performed using in silico ADMET analysis, and molecular docking information on the compounds was gained using the DS 3.5 software subprotocol. All the time, the cytotoxic effect of silver compounds was monitored for 24 h in comparison to cisplatin. The apoptotic effect of these compounds increased in cancer cells as compared to normal cells. Complex 3b exhibited the highest cytotoxic activity on cancer cell in 24 and 72 h, but complex 3a exhibited the highest cytotoxic activity on cancer cell s in 48 h. Moreover, all Ag(I)NHC complexes exhibited significant statistical difference depending on the increase in concentration on cancer cells, and all compounds induced apoptosis associated with distributing of membrane polarization and stopping the cell cycle in phase G1 and the caspase-3 activity. Caspase-3 activity of the new Ag(I)NHC compounds showed 8.3 to 17.6-fold increase compared the untreated cells. The loss of mitochondrial membrane potential indicated that JC-1 assay results were 16.9 to17.2-fold higher than normal cells in Ag(I)NHC compounds and 11.3-fold higher her in cisplatin. In addition, molecular docking studies were executed on the Ag(I)NHC complexes, and cisplatin estimate that the binding modes towards the EGFR kinase. Because epidermal growth factor receptor (EGFR) is expressed highly in a great number of epithelial tumors. These findings suggested that Ag(I)NHC complexes exhibited anticancer activity and may be considered to have a new therapeutic potential for human non-small cell lung cancer cell treatment.

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Acknowledgments

Işıl Yıldırım would like to thank all co-authors for their contributions. This work is part of Işıl Yıldırım’s Doctoral Dissertation. Therefore, she is the main author. Studies were carried out in the Anadolu University Plant Drug and Scientific Research Center (AUBIBAM), Cell Culture Laboratory.

Funding

This study was financially supported by the Inonu University Research Project Unit (Project No. the I. U. BAP 2016/166).

Author information

Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Inonu University, 44280, Malatya, Turkey

    Türkan Kutlu & Yetkin Gök

  2. Science Institute, Inonu University, 44280, Malatya, Turkey

    Işıl Yıldırım

  3. Vocational School, Pharmacy Services Program, Beykent University, 34500, Istanbul, Turkey

    Işıl Yıldırım

  4. Department of Pharmacology, Faculty of Pharmacy, Anadolu University, 26210, Eskisehir, Turkey

    Miriş Dikmen

  5. Faculty of Arts and Sciences, Department of Chemistry, Gaziantep University, 27310, Gaziantep, Turkey

    Tuğba Taskin Tok

  6. Institute of Health Sciences, Department of Bioinformatics and Computational Biology, Gaziantep University, 27310, Gaziantep, Turkey

    Tuğba Taskin Tok

  7. Health Services Vocational School, Inonu University, 44280, Malatya, Turkey

    Aydın Aktaş

Authors
  1. Türkan Kutlu
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  2. Işıl Yıldırım
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  3. Miriş Dikmen
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  4. Tuğba Taskin Tok
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  5. Aydın Aktaş
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Corresponding author

Correspondence to Aydın Aktaş.

Supplementary Information

Supplementary Information

Table S1. Interaction Types and Distances of for Erlotonib, Cisplatin, and Complexes 3a-, 3b- and 3c-EGFR

Interaction

Distance Å

Bonding

Bonding Types

Binding site of target

Binding site of ligand

A:MET769:N - A:erlotinib:N2

2.6991

Hydrogen Bond

Conventional Hydrogen Bond

A:MET769:N

A:erlotinib:N2

A:erlotinib:H16 - A:PRO770:O

2.4901

Hydrogen Bond

Carbon Hydrogen Bond

A:PRO770:O

A:erlotinib:H16

A:erlotinib:H20 - A:GLN767:O

2.0581

Hydrogen Bond

Carbon Hydrogen Bond

A:GLN767:O

A:erlotinib:H20

A:THR830:OG1 - A:erlotinib

4.0726

Hydrogen Bond

Pi-Donor Hydrogen Bond

A:THR830:OG1

A:erlotinib

A:LEU694:CD1 - A:erlotinib

3.6847

Hydrophobic

Pi-Sigma

A:LEU694:CD1

A:erlotinib

Interaction

Distance Å

Bonding

Bonding Types

Binding site of target

Binding site of ligand

A:LEU820:CD1 - A:erlotinib

3.8573

Hydrophobic

Pi-Sigma

A:LEU820:CD1

A:erlotinib

A:erlotinib - A:LYS721

4.8072

Hydrophobic

Pi-Alkyl

A:LYS721

A:erlotinib

A:erlotinib - A:ALA719

3.7388

Hydrophobic

Pi-Alkyl

A:ALA719

A:erlotinib

A:erlotinib - A:MET769

5.4440

Hydrophobic

Pi-Alkyl

A:MET769

A:erlotinib

A:erlotinib - A:ALA719

5.3493

Hydrophobic

Pi-Alkyl

A:ALA719

A:erlotinib

A:erlotinib - A:LEU820

5.3122

Hydrophobic

Pi-Alkyl

A:LEU820

A:erlotinib

Interactions

Distance Å

Bonding

Bonding Types

Binding site of target

Binding site of ligand

A:LYS721:NZ - :cisplatin:CL

4.3661

Electrostatic

Attractive Charge

A:LYS721:NZ

:cisplatin:CL

A:THR766:HG1 - :cisplatin:CL

1.8943

Hydrogen Bond; Halogen

Conventional Hydrogen Bond; Halogen (Cl, Br, I)

A:THR766:HG1

:cisplatin:CL

Interactions

Distance Å

Bonding

Bonding Types

Binding site of target

Binding site of ligand

A:LYS721:NZ - :3a:BR22

5.4602

Electrostatic

Attractive Charge

A:LYS721:NZ

:3a:BR22

A:LYS721:HZ3 - :3a:O18

1.9185

Hydrogen Bond

Conventional Hydrogen Bond

A:LYS721:HZ3

:3a:O18

:3a:H8 - A:GLN767:O

2.5549

Hydrogen Bond

Carbon Hydrogen Bond

A:GLN767:O

:3a:H8

:3a:H18 - A:ASP831:OD2

2.1550

Hydrogen Bond

Carbon Hydrogen Bond

A:ASP831:OD2

:3a:H18

:3a:H25 - A:ASP831:OD2

1.9605

Hydrogen Bond

Carbon Hydrogen Bond

A:ASP831:OD2

:3a:H25

A:VAL702 - :3a

5.1318

Hydrophobic

Alkyl

A:VAL702

:3a

A:LYS721 - :3a

5.2499

Hydrophobic

Alkyl

A:LYS721

:3a

:3a:C15 - A:CYS751

4.0161

Hydrophobic

Alkyl

A:CYS751

:3a:C15

:3a:C15 - A:MET769

4.5944

Hydrophobic

Alkyl

A:MET769

:3a:C15

:3a:C15 - A:LEU820

5.0114

Hydrophobic

Alkyl

A:LEU820

:3a:C15

:3a - A:LEU694

4.4650

Hydrophobic

Pi-Alkyl

A:LEU694

:3a

Interactions

Distance Å

Bonding

Bonding Types

Binding site of target

Binding site of ligand

A:LYS721:NZ - :3b:BR22

3.4169

Electrostatic

Attractive Charge

A:LYS721:NZ

:3b:BR22

A:LYS721:HE2 - :3b:BR22

2.4022

Hydrogen Bond

Carbon Hydrogen Bond

A:LYS721:HE2

:3b:BR22

A:MET742:SD - :3b

5.4820

Other

Pi-Sulfur

A:MET742:SD

:3b

A:THR766:OG1 - :3b

2.9356

Other

Pi-Lone Pair

A:THR766:OG1

:3b

A:LEU694 - :3b

5.4635

Hydrophobic

Alkyl

A:LEU694

:3b

A:ALA719 - :3b

4.6323

Hydrophobic

Alkyl

A:ALA719

:3b

A:LEU820 - :3b

4.5608

Hydrophobic

Alkyl

A:LEU820

:3b

:3b:C14 - A:MET742

4.0514

Hydrophobic

Alkyl

A:MET742

:3b:C14

:3b:C20 - A:LYS721

5.0173

Hydrophobic

Alkyl

A:LYS721

:3b:C20

:3b - A:ALA719

4.5899

Hydrophobic

Pi-Alkyl

A:ALA719

:3b

:3b - A:LYS721

4.1508

Hydrophobic

Pi-Alkyl

A:LYS721

:3b

:3b - A:LEU764

5.4473

Hydrophobic

Pi-Alkyl

A:LEU764

:3b

Interactions

Distance Å

Bonding

Bonding Types

Binding site of target

Binding site of ligand

Interaction

Distance Å

Bonding

Bonding Types

Binding site of target

Binding site of ligand

A:THR766:HG1 - :3c:O21

1.6837

Hydrogen Bond

Conventional Hydrogen Bond

A:THR766:HG1

:3c:O21

A:MET769:HN - :3c:O18

1.6885

Hydrogen Bond

Conventional Hydrogen Bond

A:MET769:HN

:3c:O18

:3c:H46 - A:ALA719:O

2.3530

Hydrogen Bond

Conventional Hydrogen Bond

A:ALA719:O

:3c:H46

:3c:H46 - A:LEU764:O

2.1519

Hydrogen Bond

Conventional Hydrogen Bond

A:LEU764:O

:3c:H46

A:LEU768:HA - :3c:O18

2.7141

Hydrogen Bond

Carbon Hydrogen Bond

A:LEU768:HA

:3c:O18

:3c:H17 - A:MET769:O

2.8565

Hydrogen Bond

Carbon Hydrogen Bond

A:MET769:O

:3c:H17

:3c:H24 - A:MET769:O

2.4493

Hydrogen Bond

Carbon Hydrogen Bond

A:MET769:O

:3c:H24

A:LEU694 - :3c

5.3888

Hydrophobic

Alkyl

A:LEU694

:3c

A:ALA719 - :3c

4.4772

Hydrophobic

Alkyl

A:ALA719

:3c

A:LEU768 - :3c

5.3355

Hydrophobic

Alkyl

A:LEU768

:3c

A:LEU820 - :3c

4.8223

Hydrophobic

Alkyl

A:LEU820

:3c

:3c - A:VAL702

4.4625

Hydrophobic

Pi-Alkyl

A:VAL702

:3c

:3c - A:LYS721

5.1781

Hydrophobic

Pi-Alkyl

A:LYS721

:3c

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Kutlu, T., Yıldırım, I., Dikmen, M. et al. The Cytotoxicity Profile, Apoptosis Mechanism, and Molecular Docking Studies of a Series of Benzimidazolium Derivative Morpholine-Substituted Ag(I) Heterocyclic Carbene Complexes. Pharm Chem J 57, 10–28 (2023). https://doi.org/10.1007/s11094-023-02846-9

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