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In vitro activity, stability, and lipophilicity changes of cisplatin through substitution of different amine ligands

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Abstract

In this study, several cisplatin analogs were designed to investigate the antitumor activity and lipophilicity effects in amine change. The amines of the cisplatin molecule were substituted with aliphatic amines in different analogs. The cytotoxicity of analogs against human colon cancer (HCT116) was investigated using MTT assay, and spectroscopic methods were used to determine the DNA binding mode. Cytotoxicity studies revealed cis-dichloro-dimethylamine-platinum has a lower IC50 (48.87 µM) than carboplatin (68.46 µM) and more than cisplatin (21 µM) against human colon cancer cells (HCT116), respectively. DNA denaturation study indicated that the stability of DNA in the presence of these compounds diminished and substitution of propylamine and methylamine groups increased DNA denaturation. Further, the interaction of the desired compounds with DNA proved to be a spontaneous process. Tm analysis also revealed that cisplatin, cis-dichloro-dimethylamine-platinum, and cis-dichloro-dipropylamine-platinum complexes made DNA double helix unstable via covalent bond, while cis-dichloro-dibutylamine-platinum and cis-dichloro-diisobutylamine-platinum stabilized DNA via electrostatic binding to DNA. The results of fluorescence studies showed that the quenching nature of cisplatin and methyl and propyl systems was dynamic, while the static quenching was observed in the presence of cis-dichloro-dibutylamine-platinum and cis-dichloro-diisobutylamine-platinum. The molecular docking simulations and DFT analysis were performed to investigate the binding sites and chemical behavior of cisplatin analogs, respectively. Molecular docking demonstrated that except cis-dichloro-diisobutylamine-platinum, other complexes had higher negative docking energy than cisplatin for interaction with DNA, and methyl and propyl complexes may be good candidates for anticancer drugs.

Graphical abstract

Some anticancer Pt(II) complexes as cisplatin analogs were synthesized with aliphatic amines to investigate the lipophilicity effects. In vitro cytotoxicity effects were tested against human colon cancer (HCT116). Moreover, the modes of DNA binding with synthesized compounds were investigated using fluorescence spectra, DFT and molecular docking.

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Abbreviations

DNA:

Deoxyribonucleic acid

EB:

Ethidium bromide

CT-DNA:

Calf thymus DNA

DFT:

Density functional theory

ADT:

AutoDock tools

HOMO:

Highest occupied molecular orbital

LUMO:

Lowest unoccupied molecular orbital

NBO:

Natural orbital bond analysis

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Acknowledgements

The authors would like to gratefully appreciate the Chemistry & Chemical Engineering Research Center of Iran for financially supporting this project. Also, the authors would like to thank Dr. Samaneh Zolghadri from the Department of Biology, Islamic Azad University, Jahrom Branch, Fars province, Iran, for her advices in analyzing the cytotoxicity results.

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Authors and Affiliations

  1. Chemistry & Chemical Engineering Research Center of Iran, Tehran, Iran

    Arezo Rahiminezhad, Mahboube Eslami Moghadam & A. Wahid Mesbah

  2. Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran

    Adeleh Divsalar

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  1. Arezo Rahiminezhad
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  2. Mahboube Eslami Moghadam
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Correspondence to Mahboube Eslami Moghadam.

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Rahiminezhad, A., Eslami Moghadam, M., Divsalar, A. et al. In vitro activity, stability, and lipophilicity changes of cisplatin through substitution of different amine ligands. J IRAN CHEM SOC 19, 2749–2768 (2022). https://doi.org/10.1007/s13738-022-02491-1

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