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

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.

Anti-glioblastoma Effects of Structural Variants of Benzoylphenoxyacetamide (BPA): II. Synthesis Strategies for Phenolic Variants of BPAs With Potential for Blood Brain Barrier Penetration.

“…As a result of this initial screening, we have identified two lead drug candidates, HR51 and HR59, with phenolic moieties that contain BPA structural skeleton similar to our prototype anti-glioblastoma compound PP1 26 . This is in addition to our recently reported BPA-based compounds (HR28, HR32, HR37, and HR46), which also demonstrated high potential as anti-glioblastoma drugs 31 . Anti-glioblastoma effects of HR51 and HR59 were subsequently confirmed using four different human glioblastoma cell lines, LN229, U-87 MG, U-118 MG, T98G, and the cytotoxicity data were compared to normal human astrocytes (NHA).…”

“…The starting point for the preparation of all phenolic BPAs is fenofibric acid (FFA), and the corresponding aminophenol or aminonaphthol residues (Scheme 3) are added through amide (peptide) coupling reactions 35,36 . As previously reported 31 , due to the steric hindrance of the carboxylic group of FFA, which includes two methyl groups in the alpha position of carboxylic acid, combined with the lower amine nucleophilicity of anilines in DCC-or EDC-coupling, these reactions do not produce acceptable isolated yields. This occurs even with more reactive aminophenols and EDC or DCC, which are stronger nucleophiles compared to nonactivated anilines, which is expected to produce corresponding BPA compounds in acceptable yields 37 .…”

“…Overall Chemical Design: In our previous studies we have explored the importance of a basic BPA skeleton 31 , and concluded that BPA could serve as a "pharmacophore", necessary to retain anti-glioblastoma activity 32,33 . The amide part of the BPA skeleton can be specifically modelled to obtain a more desirable anti-tumor activity.…”

“…All starting materials were reagent grade and purchased from Sigma-Aldrich, ArkPharm, and TCI America. 1 H-NMR spectra were recorded on Varian Mercury 300 and Varian Mercury 400 Plus instruments in CDCl3 and DMSO-d6, using the solvent chemical shifts as an internal standard 31 . All computed molecular descriptors were generated by ChemAxon MarvinSketch version 19.20.…”

“…Comparison between FF, FFA, and PP1 structural and anti-cancer properties. The information regarding the compounds water solubility, stability in human blood, and in vitro cytotoxicitywere previously reported31 . *determined using LN229 monolayer cultures and MTT assay.…”