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Synthesis of berberine-piperazine conjugates as potential antioxidant and cytotoxic agents

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Abstract

Piperazine derivatives bearing different electron-withdrawing and electron-donating functional groups were linked to the well-known isoquinoline alkaloid derivative, berberine via efficient organic transformations. The entire target berberine-based analogues were examined for their in vitro antioxidant potency using 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid bioassays, and anticancer activities using sulforhodamine B assay against HeLa and CaSki cervical cancer cell lines in addition to the cytotoxicity using Madin-Darby canine kidney non-cancer cell lines and, ascorbic acid and berberine used as a control for antioxidant and anticancer activities, respectively. Bioassay results revealed that newer compounds were more active against CaSki and HeLa cell lines with therapeutic indices better than that of parent berberine and showed tolerable cytotoxicity to the normal cells. A final analogue 5a with 4-methylpiperazine substituent indicated most significant anticancer potency with a therapeutic index of 58.53 (HeLa) and 48.76 (CaSki), followed by those bearing meta-chloropiperazine rings with a therapeutic index of 41.83 (HeLa) and 47.35 (CaSki), respectively.In addition, newly synthesized analogues exerted a significant radical scavenging activity against 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid cation with IC50 values of 8.917 µg/mL, and were good to moderate scavengers of 2,2-diphenyl-1-picrylhydrazyl radical with IC50 values of 25.40 µg/mL. Synthesized compound was characterized using several techniques, fourier transform infrared spectroscopy, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, mass spectroscopy and elemental (CHN) analyses.

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Acknowledgments

This article was supported by the KU Research Professor Program of Konkuk University, Seoul, South Korea.

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Authors and Affiliations

  1. Organic Research Laboratory, Department of Bioresources and Food Sciences, College of Life and Environmental Sciences, Konkuk University, Seoul, South Korea

    Bhupendra Mistry, Young Soo Keum, Muthuraman Pandurangan & Doo Hwan Kim

  2. Department of Food Science and Biotechnology, Dongguk University, Biomedical Campus, 32 Dongguk-ro, Ilsandong-gu, Goyang-si, Gyenggi-do, Republic of Korea

    Rahul V. Patel

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  1. Bhupendra Mistry
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  2. Young Soo Keum
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  3. Muthuraman Pandurangan
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  4. Rahul V. Patel
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  5. Doo Hwan Kim
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Correspondence to Bhupendra Mistry or Doo Hwan Kim.

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Mistry, B., Keum, Y.S., Pandurangan, M. et al. Synthesis of berberine-piperazine conjugates as potential antioxidant and cytotoxic agents. Med Chem Res 25, 2461–2470 (2016). https://doi.org/10.1007/s00044-016-1662-3

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  • DOI: https://doi.org/10.1007/s00044-016-1662-3

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