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Novel vitamin K3 analogs containing 3-N-substituted aromatic and piperazine rings with selective in vitro anticancer activity against HeLa, U87 MG, and MCF-7 cells

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Abstract

In this study, firstly, novel vitamin K3 analogs were synthesized by the reactions of vitamin K3 (2-methyl-1,4-naphthoquinone, also known as menadione) with some aromatic and heterocyclic ring substituted nucleophiles such as 2,4-dimethoxyaniline, 4-methoxyaniline, 4-benzylpiperidine and 1-(2-aminoethyl)piperazine in ethanol/Na2CO3, and 1-(diphenylmethyl)piperazine in chloroform/triethylamine (TEA) at room temperature. Their structures were elucidated by Fourier transform infrared spectroscopy (FT-IR), 1H nuclear magnetic resonance (1H NMR), attached proton test nuclear magnetic resonance (APT-NMR) and mass spectrometry (MS). Secondly, in vitro cytotoxic effects of vitamin K3 analogs were investigated by MTT assay against three cancer cell lines (HeLa, U87 MG, and MCF-7) to evaluate their anticancer activity and a human embryonic kidney cell line (HEK-293) to check their cancer cell selectivity. One of the compounds, namely 2-((2,4-dimethoxyphenyl)amino)-3-methylnaphthalene-1,4-dione(5), was found to inhibit the growth of HeLa cervical cancer cells selectively, even better than vitamin K3, at a non-toxic concentration for healthy cells. The selectivity index of this compound for HeLa cells was calculated approximately as “3”. Vitamin K3 was more effective against U87 MG and MCF-7 cells than its derivatives, moreover it was the only compound, which was significantly toxic to breast cancer cells, but its selectivity was poor. Furthermore, anticancer properties of piperazine derivatives of vitamin K3 were investigated by us for the first time in this study.

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Novel vitamin K3 analogs containing 3-N-substituted aromatic and piperazine rings with selective in vitro anticancer activity against HeLa, U87 MG, and MCF-7 cells

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Acknowledgements

We gratefully thank the Research Fund of Istanbul University-Cerrahpasa for financial support of this work (Project Numbers: FDK-2017-24871).

Author contributions

AFSHA: Co-Author. The synthesis, purification and characterization of novel vitamin K3 analogs by using spectroscopic techniques. NGD: Co-Author. The synthesis, purification and characterization of novel vitamin K3 analogs by using spectroscopic techniques. CS*: Corresponding author. The synthesis, purification and characterization of novel vitamin K3 analogs by using spectroscopic techniques. EO-U: Co-Author. The determination of cytotoxic effects of novel vitamin K3 analogs. EM: Co-Author. The determination of cytotoxic effects of novel vitamin K3 analogs. NA: Co-Author. The determination of cytotoxic effects of novel vitamin K3 analogs.

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Authors and Affiliations

  1. Istanbul University-Cerrahpasa, Engineering Faculty, Department of Chemistry, Division of Organic Chemistry, Avcilar, 34320, Istanbul, Turkey

    Aesha F. S. H. Abdassalam, Nahide Gulsah Deniz & Cigdem Sayil

  2. Al Zawia University, Faculty of Science, Department of Chemistry, Zawia, Libya

    Aesha F. S. H. Abdassalam

  3. Istanbul University, Faculty of Science, Department of Molecular Biology and Genetics, Istanbul, Turkey

    Evren Onay-Ucar, Elif Mertoglu & Nazli Arda

  4. Istanbul University, Center for Research and Practice in Biotechnology and Genetic Engineering, Istanbul, Turkey

    Nazli Arda

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  1. Aesha F. S. H. Abdassalam
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Correspondence to Cigdem Sayil.

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Abdassalam, A.F.S.H., Deniz, N.G., Sayil, C. et al. Novel vitamin K3 analogs containing 3-N-substituted aromatic and piperazine rings with selective in vitro anticancer activity against HeLa, U87 MG, and MCF-7 cells. Med Chem Res 32, 475–484 (2023). https://doi.org/10.1007/s00044-023-03019-9

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