Syntheses of mono-acylated luteolin derivatives, evaluation of their antiproliferative and radical scavenging activities and implications on their oral bioavailability

Stephen Lo,Bruno Fedrizzi,David Barker,Euphemia Leung

doi:10.1038/s41598-021-92135-w

Abstract

Luteolin is a flavonoid found in a wide range of plant materials, including commonly eaten fruits and vegetables. It displays a wide range of biological activities but is known to have poor bioavailability. In this study, ten different mono-acyl (nine 5-O-acyl and one 7-O-acyl) derivatives of luteolin were synthesised for the purpose of improving bioactivity and bioavailability, and therefore enhance their therapeutic potential. The antiproliferative activity of these derivatives was assessed against the HCT116 colon cancer and MDA-MB-231 breast cancer cell lines using a 3[H] thymidine incorporation assay. The radical scavenging activity of these derivatives against 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cation and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical using Trolox as a standard, was also assessed. Some of these derivatives were found to have improved antiproliferative activity with comparable radical scavenging activity compared to luteolin. Increased lipophilicity has been shown to increase the bioavailability of flavonoids implying these analogues will also have increased bioavailability.

Highlights

Luteolin is a flavonoid found in a wide range of plant materials, including commonly eaten fruits and vegetables
The addition of a range of acyl chlorides to compound 2, in the presence of triethylamine afforded the 5-O-acyl tri-O-benzyl luteolin derivatives (3a–i) in 55–82% yields (Table 1). These tetra-substituted luteolin products were immediately identified on thin layer chromatography (TLC) by their blue fluorescence under both short (254 nm) and long (365 nm) wavelengths
It was generally found that the 5-O acyl derivatives with aliphatic chains displayed better antiproliferative activity against the cancer cell lines as well as retained similar radical scavenging activities compared to luteolin This suggested that the antiproliferative activity of these derivatives is unrelated to the radical scavenging activity

Summary

Introduction

Luteolin is a flavonoid found in a wide range of plant materials, including commonly eaten fruits and vegetables. Luteolin displays a wide range of bioactivities which strongly suggests that the compound has potential for further development into agents with health-promoting effects. Studies have reported luteolin’s ability to inhibit proliferation against many cancer cell lines, and have potential utility in the treatment of c ancer[13,14,15,16,17,18,19,20] Despite these promising bioactivities, a problem that is ubiquitous to all flavonoid compounds which severely limits their therapeutic ability is their poor oral bioavailability or ability to reach site of action after oral administration[21,22,23]. These derivatives were evaluated for their antiproliferative and radical scavenging activities to determine the effects that substitution of the hydroxy groups with the more lipophilic moieties had on its therapeutic ability

Methods

Results

Conclusion