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 - UTU Research Portal

A1 Refereed original research article in a scientific journal

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

Authors: Matovic Jelena, Järvinen Juulia, Sokka Iris K, Imlimthan Surachet, Raitanen Jan-Erik, Montaser Ahmed, Maaheimo Hannu, Huttunen Kristiina M, Peräniemi Sirpa, Airaksinen Anu J, Sarparanta Mirkka, Johansson Mikael P, Rautio Jarkko, Ekholm Filip S

Publisher: AMER CHEMICAL SOC

Publication year: 2021

Journal: Molecular Pharmaceutics

Journal name in source: MOLECULAR PHARMACEUTICS

Journal acronym: MOL PHARMACEUT

Volume: 18

Issue: 1

First page : 285

Last page: 304

Number of pages: 20

ISSN: 1543-8384

eISSN: 1543-8392

DOI: https://doi.org/10.1021/acs.molpharmaceut.0c00917

Self-archived copy’s web address: https://researchportal.helsinki.fi/en/publications/exploring-the-biochemical-foundations-of-a-successful-glut1-targe

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.