Abstract
Structural variations of the benzylphenoxyacetamide (BPA) molecular skeleton were explored as a viable starting point for designing new anti-glioblastoma drug candidates. Hand-to-hand computational evaluation, chemical modifications, and cell viability testing were performed to explore the importance of some of the structural properties in order to generate, retain, and improve desired anti-glioblastoma characteristics. It was demonstrated that several structural features are required to retain the anti-glioblastoma activity, including a carbonyl group of the benzophenone moiety, as well as 4′-chloro and 2,2-dimethy substituents. In addition, the structure of the amide moiety can be modified in such a way that desirable anti-glioblastoma and physical properties can be improved. Via these structural modifications, more than 50 compounds were prepared and tested for anti-glioblastoma activity. Four compounds were identified (HR28, HR32, HR37, and HR46) that in addition to HR40 (PP1) from our previous study, have been determined to have desirable physical and biological properties. These include high glioblastoma cytotoxicity at low μM concentrations, improved water solubility, and the ability to penetrate the blood brain barrier (BBB), which indicate a potential for becoming a new class of anti-glioblastoma drugs.
Highlights
Glioblastoma is the most aggressive and prevalent malignancy of the central nervous system (CNS), with a median patient survival rate of about 18 months[1,2,3,4]
FF is a common lipid-lowering pro-drug that following its processing by blood and tissue esterases is converted to fenofibric acid (FAA), a potent agonist of peroxisome proliferator activated receptor alpha (PPARα) that upregulates fatty acid utilization and attenuates glycolysis[23,24,25,26]
FF shows promising anti-glioblastoma activity at 50 μM, this compound is an isopropyl ester that is promptly hydrolyzed into fenofibric acid (FFA) by blood and tissue esterases[46]
Summary
Glioblastoma is the most aggressive and prevalent malignancy of the central nervous system (CNS), with a median patient survival rate of about 18 months[1,2,3,4]. We have selected the benzylphenoxyacetamide (BPA) molecular skeleton as a basis for designing new more potent anti-glioblastoma compounds due to its structural similarity to FF, as well as its increased water solubility and higher resistance to hydrolysis MPA results presented in Fig. 3 confirm our postulate that the simple amides of FFA are viable structural motifs for exploring and possibly improving the anti-glioblastoma activity of FF.
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