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Synthesis of a “clickable” Angiopep-conjugated p-coumaric acid for brain-targeted delivery

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Abstract

Overexpression of free radicals in the brain is emerging as important markers in the etiology of neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, and stroke. Numerous antioxidants with protective effect on neuronal injuries under oxidative stress are often limited to penetrate the blood–brain barrier (BBB). Angiopep-2 is the ligand of low-density lipoprotein receptor-related protein expressed on the BBB possessing high transcytosis capacity and parenchymal accumulation. In this study, novel Angiopep-conjugated p-coumaric acid (3) was synthesized, using the Click chemistry, as a potential antioxidant for the protection of the brain under oxidative stress. The clickable Angiopep (3) was synthesized by Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of the terminal acetylene-modified Angiopep and azide of p-coumaric acid. The Angiopep-conjugated compound (3) showed antioxidant potency and non-cytotoxic effect toward brain endothelial cells (BECs). Obviously, the penetration and BECs protection of 3 were higher than that of the unconjugated p-coumaric acid. The results establish the bio-conjugation of antioxidant and Angiopep with enhanced protective effect on the BECs under oxidative stress. The findings provide great potential for the development of neurotherapeutics with increased brain penetration.

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Acknowledgements

We would like to acknowledge the Faculty of Medical Technology, Mahidol University for facilities and supports. This research project is supported by Mahidol University.

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Authors and Affiliations

  1. Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, 10700, Thailand

    Thummaruk Suksrichavalit & Supaluk Prachayasittikul

  2. Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, Bangkok, 10700, Thailand

    Thummaruk Suksrichavalit

  3. Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, 10700, Thailand

    Chartchalerm Isarankura Na Ayudhya & Virapong Prachayasittikul

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  1. Thummaruk Suksrichavalit
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Correspondence to Virapong Prachayasittikul.

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Suksrichavalit, T., Prachayasittikul, S., Isarankura Na Ayudhya, C. et al. Synthesis of a “clickable” Angiopep-conjugated p-coumaric acid for brain-targeted delivery. J Mater Sci 49, 8204–8213 (2014). https://doi.org/10.1007/s10853-014-8529-0

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  • DOI: https://doi.org/10.1007/s10853-014-8529-0

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