Document Type
Article
Publication Date
7-28-2023
Publication Title
Scientific Reports
Abstract
Glioblastomas are highly aggressive brain tumors for which therapeutic options are very limited. In a quest for new anti-glioblastoma drugs, we focused on specific structural modifications to the benzoyl-phenoxy-acetamide (BPA) structure present in a common lipid-lowering drug, fenofibrate, and in our first prototype glioblastoma drug, PP1. Here, we propose extensive computational analyses to improve the selection of the most effective glioblastoma drug candidates. Initially, over 100 structural BPA variations were analyzed and their physicochemical properties, such as water solubility (− logS), calculated partition coefficient (ClogP), probability for BBB crossing (BBB_SCORE), probability for CNS penetration (CNS-MPO) and calculated cardiotoxicity (hERG), were evaluated. This integrated approach allowed us to select pyridine variants of BPA that show improved BBB penetration, water solubility, and low cardiotoxicity. Herein the top 24 compounds were synthesized and analyzed in cell culture. Six of them demonstrated glioblastoma toxicity with IC50 ranging from 0.59 to 3.24 µM. Importantly, one of the compounds, HR68, accumulated in the brain tumor tissue at 3.7 ± 0.5 µM, which exceeds its glioblastoma IC50 (1.17 µM) by over threefold.
PubMed ID
37507404
Volume
13
Issue
1
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Ingraham, Charles H.; Stalinska, Joanna; Carson, Sean C.; Colley, Susan B.; Rak, Monika; Lassak, Adam; Peruzzi, Francesca; Reiss, Krzysztof; and Jursic, Branko S., "Computational modeling and synthesis of pyridine variants of benzoyl-phenoxy-acetamide with high glioblastoma cytotoxicity and brain tumor penetration" (2023). School of Graduate Studies Faculty Publications. 137.
https://digitalscholar.lsuhsc.edu/sogs_facpubs/137