Exploring the Biochemical Foundations of a Successful GLUT1-Targeting Strategy to BNCT: Chemical Synthesis and in Vitro Evaluation of the Entire Positional Isomer Library of ortho-Carboranylmethyl-Bearing Glucoconjugates

Jelena Matović, Juulia Järvinen, Iris K. Sokka, Surachet Imlimthan, Jan Erik Raitanen, Ahmed Montaser, Hannu Maaheimo, Kristiina M. Huttunen, Sirpa Peräniemi, Anu J. Airaksinen, Mirkka Sarparanta, Mikael P. Johansson, Jarkko Rautio, Filip S. Ekholm (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Boron neutron capture therapy (BNCT) is a noninvasive binary therapeutic modality applicable to the treatment of cancers. While BNCT offers a tumor-targeting selectivity that is difficult to match by other means, the last obstacles preventing the full harness of this potential come in the form of the suboptimal boron delivery strategies presently used in the clinics. To address these challenges, we have developed delivery agents that target the glucose transporter GLUT1. Here, we present the chemical synthesis of a number of ortho-carboranylmethyl-substituted glucoconjugates and the biological assessment of all positional isomers. Altogether, the study provides protocols for the synthesis and structural characterization of such glucoconjugates and insights into their essential properties, for example, cytotoxicity, GLUT1-affinity, metabolism, and boron delivery capacity. In addition to solidifying the biochemical foundations of a successful GLUT1-targeting approach to BNCT, we identify the most promising modification sites in d-glucose, which are critical in order to further develop this strategy toward clinical use.

Original languageEnglish
Pages (from-to)285-304
Number of pages20
JournalMolecular Pharmaceutics
Volume18
Issue number1
DOIs
Publication statusPublished - 4 Jan 2021
MoE publication typeA1 Journal article-refereed

Keywords

  • boron neutron capture therapy
  • cancer therapeutics
  • carbohydrates
  • drug delivery
  • glucose transporters
  • medicinal chemistry

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