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Synthesis and in vitro evaluation of BBB permeability, tumor cell uptake, and cytotoxicity of a series of carboranylporphyrin conjugates.

Bhupathiraju, N. V. S. Dinesh K.; Hu, Xiaoke; Zhou, Zehua; Fronczek, Frank R.; Couraud, Pierre-Olivier; Romero, Ignacio A.; Weksler, Babette and Vicente, M. Graça H. (2014). Synthesis and in vitro evaluation of BBB permeability, tumor cell uptake, and cytotoxicity of a series of carboranylporphyrin conjugates. Journal of Medicinal Chemistry, 57(15) pp. 6718–28.

DOI (Digital Object Identifier) Link: https://doi.org/10.1021/jm500786c
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Abstract

A series of tri[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin conjugates of linear and branched polyamines, glucose, arginine, tri(ethylene glycol), and Tyr-D-Arg-Phe-β-Ala (YRFA) peptide were synthesized. These conjugates were investigated for their BBB permeability in human hCMEC/D3 brain endothelial cells, and their cytotoxicity and uptake were assessed using human glioma T98G cells. For comparison purposes, a symmetric tetra[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin was also synthesized, and its crystal structure was obtained. All porphyrin conjugates show low dark cytotoxicity (IC50>400 μM) and low phototoxicity (IC50>100 μM at 1.5 J/cm2) toward T98G cells. All conjugates were efficiently taken up by T98G cells, particularly the cationic polyamine and arginine conjugates, and were localized in multiple cellular organelles, including mitochondria and lysosomes. All compounds showed relatively low in vitro BBB permeability compared with that of lucifer yellow because of their higher molecular weight, hydrophobicity, and tendency for aggregation in solution. Within this series, the branched polyamine and YRFA conjugates showed the highest permeability coefficient, whereas the glucose conjugate showed the lowest permeability coefficient.

Item Type: Journal Item
Copyright Holders: 2014 American Chemical Society
ISSN: 1520-4804
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 42434
Depositing User: Ignacio A Romero
Date Deposited: 14 Apr 2015 08:18
Last Modified: 07 Dec 2018 10:29
URI: http://oro.open.ac.uk/id/eprint/42434
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