Anti-glioblastoma effects of phenolic variants of benzoylphenoxyacetamide (BPA) with high potential for blood brain barrier penetration

Joanna Stalinska,Susan B Colley,Cecilia Vittori,Krzysztof Reiss,Karlie Plaisance-Bonstaff,Adam Lassak,Branko S Jursic,Francesca Peruzzi,Charles H Ingraham Iv,Sean C Carson,Celeste Faia

doi:10.1038/s41598-022-07247-8

Abstract

Glioblastomas are the most aggressive brain tumors for which therapeutic options are limited. Current therapies against glioblastoma include surgical resection, followed by radiotherapy plus concomitant treatment and maintenance with temozolomide (TMZ), however, these standard therapies are often ineffective, and average survival time for glioblastoma patients is between 12 and 18 months. We have previously reported a strong anti-glioblastoma activity of several metabolic compounds, which were synthetized based compounds, which were synthetized based on the chemical structure of a common lipid-lowering drug, fenofibrate, and share a general molecular skeleton of benzoylphenoxyacetamide (BPA). Extensive computational analyses of phenol and naphthol moieties added to the BPA skeleton were performed in this study with the objective of selecting new BPA variants for subsequent compound preparation and anti-glioblastoma testing. Initially, 81 structural variations were considered and their physical properties such as solubility (logS), blood–brain partitioning (logBB), and probability of entering the CNS calculated by the Central Nervous System—Multiparameter Optimization (MPO-CNS) algorithm were evaluated. From this initial list, 18 compounds were further evaluated for anti-glioblastoma activity in vitro. Nine compounds demonstrated desirable glioblastoma cell toxicity in cell culture, and two of them, HR51, and HR59 demonstrated significantly improved capability of crossing the model blood–brain-barrier (BBB) composed of endothelial cells, astrocytes and pericytes.

Highlights

Glioblastomas are the most aggressive brain tumors for which therapeutic options are very limited[1,2]
glioma initiating cells (GICs) express ATP binding cassette (ABC) transporter proteins, which mediate extensive drug efflux contributing to radio- and chemo-resistance25, neovascularization[26], and invasiveness[27]; Fourth, early diagnosis of glioblastoma is rare, large highly infiltrating and vascularized tumors are often present at the time of d iagnosis[28]; Fifth, the optimization of clinical protocols for glioblastoma treatment requires the use of a reliable preclinical model/s
We have previously reported that 50 μM fenofibrate (FF) has a strong anti-glioblastoma activity in cell culture, and in glioblastoma mouse models following intratumoral injection[41] (Fig. 1)

Summary

Introduction

Glioblastomas are the most aggressive brain tumors for which therapeutic options are very limited[1,2]. This is critical for the initial screening of a large number of compounds, including BPA variants, and for selection of best candidates for subsequent measurements of intracranial tumor drug penetration and anti-tumoral efficacy.

Results

Conclusion