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Potent antiproliferative active agents: novel bis Schiff bases and bis spiro β-lactams bearing isatin tethered with butylene and phenylene as spacer and DNA/BSA binding behavior as well as studying molecular docking

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Abstract

A [2+2]-cycloaddition of bis-isatin Schiff bases 5a–b and 7 with activated aryloxyacetic acid derivatives 8a–d afforded bis-spiroisatino β-lactams with aliphatic and aromatic spacers. The structures of the synthesized 2-oxindoles and spirooxindoles were determined based on Fourier-transform infrared spectroscopy, proton-1 and carbon-13 nuclear magnetic resonance spectroscopies and CHN analysis. Our interest in these bis-Schiff bases and bis-spiroisatino β-lactams is for their potential anticancer capabilities. In vitro bioactivity testing against the cervical adenocarcinoma (HeLa) and breast cancer (MCF-7) cell lines as well as noncancerous NIH/3T3 fibroblast cell was investigated applying the MTT assay. Bis-isatin derivatives 5a, 5b, 9h, 10a, and 10b showed promising antiproliferative activity toward these two cancer cell lines. Two of the bis-isatin Schiff bases, 5a and 5b, displayed IC50 values less than that of the clinically-used anticancer agent cisplatin towards both the MCF-7 and HeLa cells, while several of the bis-isatin β-lactams showed similar bioactivity to that of cisplatin. All of the oxindoles and spirooxindoles displayed a selective anticancer effect except 10b. To study the possible mechanism for this bioactivity, DNA and BSA binding analyses were performed using fluorescence and UV–visible spectroscopic techniques. The isatin adducts displayed excellent interaction propensity to CT-DNA as well as BSA. Molecular docking investigation carried out on DNA and BSA with promising molecules to show the possible mechanism of cytotoxicity activities.

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Acknowledgements

The authors would like to thank the Shiraz University Research Council for financial support (Grant no. 97-GR-SC-23).

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Authors and Affiliations

  1. Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71946-84795, Iran

    Mohammad Bashiri, Aliasghar Jarrahpour, S. Masoud Nabavizadeh & Elahe Haddadi

  2. School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, 71348-14336, Iran

    Somaye Karimian

  3. School of Paramedical Science, Diagnostic Laboratory Science and Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Banafsheh Rastegari

  4. Center for Molecular Diversity in Drug Design, Discovery, and Delivery, Department of Chemistry, University of South Florida, 4202 E, Fowler Avenue, CHE 205, Tampa, FL, USA

    Edward Turos

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Bashiri, M., Jarrahpour, A., Nabavizadeh, S.M. et al. Potent antiproliferative active agents: novel bis Schiff bases and bis spiro β-lactams bearing isatin tethered with butylene and phenylene as spacer and DNA/BSA binding behavior as well as studying molecular docking. Med Chem Res 30, 258–284 (2021). https://doi.org/10.1007/s00044-020-02659-5

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