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Design, synthesis, characterization and cytotoxic activity of new ortho-hydroxy and indole-chalcone derivatives against breast cancer cells (MCF-7)

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Abstract

Twenty-seven new ortho-hydroxy chalcone and a series of indole-chalcone derivatives have been designed and synthesized. The structures of all newly-synthesized compounds were characterized by different spectroscopic techniques and the interactions with tubulin were evaluated for antiproliferative activities in vitro. The structure–activity relationships were elucidated for compounds with various substituents on the benzene ring of the aldehyde moiety at positions C-3, C-4 and C-5 with constant o-OH. The best inhibition results of ring bioisoterism for cancer cell growth were obtained for compounds 4c, 5j, and 6a with substituents m-tBu, Br and p-OCH3, respectively. Their antiproliferative activity was evaluated in MCF-7 cells, with compound 5j showing cytotoxicity activity comparable to that of reference compound paclitaxel. A computational study was carried out, for calculation of pharmacophore pattern, prediction of pharmacokinetic properties and toxicity. The results of the target compounds are followed by docking studies that have provided structural recommendations for designing new antiproliferative chalcones.

Highlights

  • A new series of ortho-hydroxy chalcones (4a–6j) and a series of indole chalcones (9a–d) were designed and synthesized.

  • 5-Nitrochalcone (7a–c) were readily reduced to amine to increase solubility in biological media.

  • A bioisosteric replacement was found to have enhanced in vitro inhibition potential.

  • The binding mode of Colchicine and the ortho-hydroxy chalcone derivatives to tubulin has been compared.

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Acknowledgements

Funding

The authors would like to thank the Malaysian Government for the Fundamental Research Grant Scheme (FRGS) with project code FRGS/1/2019/STG01/USM/02/16 which was used to finance this research work.

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Authors and Affiliations

  1. School of Chemical Sciences, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia

    Maadh Jumaah, Melati Khairuddean & Mohamad Nurul Azmi Mohamad Taib

  2. Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia

    Sohaib Jumaah Owaid

  3. Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603, Kuala Lumpur, Malaysia

    Nurhisyam Zakaria & Noor Hasima Nagoor

  4. Centre for Research in Biotechnology of Agriculture (CEBAR), Universiti Malaya, 50603, Kuala Lumpur, Malaysia

    Norhafiza Mohd Arshad & Noor Hasima Nagoor

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  1. Maadh Jumaah
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Correspondence to Melati Khairuddean.

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Jumaah, M., Khairuddean, M., Owaid, S.J. et al. Design, synthesis, characterization and cytotoxic activity of new ortho-hydroxy and indole-chalcone derivatives against breast cancer cells (MCF-7). Med Chem Res 31, 517–532 (2022). https://doi.org/10.1007/s00044-021-02834-2

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