Exploring anticancer activity of structurally modified benzylphenoxyacetamide (BPA); I: Synthesis strategies and computational analyses of substituted BPA variants with high anti-glioblastoma potential

• Published in: Scientific reports Vol. 9; no. 1; pp. 17021 - 17
• Main Authors: Stalinska, Joanna, Houser, Lisa, Rak, Monika, Colley, Susan B., Reiss, Krzysztof, Jursic, Branko S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-11-2019; Nature Publishing Group
• Subjects: 101/58; 13/106; 631/154/309/2144; 692/4028/67/1922; Acetamides - pharmacology; Antineoplastic Agents - pharmacology; Antitumor activity; Benzophenone; Biological properties; Blood-Brain Barrier; Brain cancer; Brain Neoplasms - drug therapy; Carbonyl compounds; Caustic soda; Cell Line, Tumor; Cell Survival - drug effects; Cell viability; Clinical trials; Computational neuroscience; Cytotoxicity; Drug development; Drug Discovery - methods; Drug Screening Assays, Antitumor - methods; Drugs; Fenofibrate - pharmacology; Glioblastoma; Glioblastoma - drug therapy; Humanities and Social Sciences; Humans; Lipids; Molecular Conformation; Mortality; multidisciplinary; Phenols; Physical properties; Respiration; Science; Science (multidisciplinary); Sodium; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-53207-0

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.