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Design, synthesis, cytotoxicity and molecular modeling studies of some novel fluorinated pyrazole-based heterocycles as anticancer and apoptosis-inducing agents

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Abstract

3,5-Diamino-4-(3-trifluoromethylphenyldiazenyl)-1H-pyrazole was used as a starting scaffold for the synthesis of new pyrazole-based heterocycles to study their effects on the proliferation of three human cancer cell lines; human liver carcinoma cell line (HepG-2), colon cancer cell line (HCT-116) and human breast cancer cell line (MCF-7) using MTT assay. The synthesized compounds were characterized on the basis of IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis results. Cytotoxicity assay results revealed that some of the compounds showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.64–7.73 μg/mL. Breast cancer cells were used for further detailed studies to understand the mechanism of cell growth inhibition and apoptosis-inducing effect of the most active compounds. The results indicated that compounds 3a, 10b and 11a arrested MCF-7 cells at G2/M phase of the cell cycle and might induce apoptosis via caspase-3-dependent pathway. Molecular modeling and binding mode analysis of the most active compounds to caspase 3 active site further provide a synergistic mechanism for their pro-apoptotic effects. In order to explore the structural requirements controlling the observed cytotoxic properties, 3D pharmacophore model was generated.

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Authors and Affiliations

  1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt

    Eman A. Fayed & Nirvana A. Gohar

  2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University (Girls), Cairo, Egypt

    Sally I. Eissa

  3. Faculty of Pharmacy, Al-Maarefa University for Science and Technology, Riyadh, Kingdom of Saudi Arabia

    Sally I. Eissa

  4. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt

    Ashraf H. Bayoumi

  5. Department of Zoology, Faculty of Science, Al-Azhar University, Cairo, Egypt

    Ahmed B. M. Mehany

  6. Organic Chemistry Department, Faculty of Science (Boys), Al-Azhar University, Cairo, Egypt

    Yousry A. Ammar

Authors
  1. Eman A. Fayed
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  2. Sally I. Eissa
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  4. Nirvana A. Gohar
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Correspondence to Sally I. Eissa.

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Fayed, E.A., Eissa, S.I., Bayoumi, A.H. et al. Design, synthesis, cytotoxicity and molecular modeling studies of some novel fluorinated pyrazole-based heterocycles as anticancer and apoptosis-inducing agents. Mol Divers 23, 165–181 (2019). https://doi.org/10.1007/s11030-018-9865-9

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  • DOI: https://doi.org/10.1007/s11030-018-9865-9

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