Synthesis and Biochemical Evaluation of Baicalein Prodrugs.

Sang-Hyun Son,Kiho Lee,Myunghwan Ahn,Jinhong Kang,Ki Yong Lee,Young Ho Jeon,Yong Woo Jung,Youngjoo Byun,Soyeon Nam

doi:10.3390/pharmaceutics13091516

Sang-Hyun Son, Kiho Lee + Show 7 more

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https://doi.org/10.3390/pharmaceutics13091516

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Journal: Pharmaceutics	Publication Date: Sep 19, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: Korea University

Abstract

Baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one), a flavonoid analog from Scutellaria baicalensis, possesses several pharmacological activities including antioxidant, antiproliferative, and anti-inflammatory activities. We previously reported that baicalein inhibits the thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) signaling pathways and can be used as an active ingredient in the treatment of asthma and atopic dermatitis. However, baicalein is rapidly metabolized to baicalin and baicalein-6-O-glucuronide in vivo, which limits its preclinical and clinical use. In this study, we designed, synthesized, and evaluated baicalein prodrugs that protect the OH group at the 7-position of the A ring in baicalein with the amino acid carbamate functional group. Comprehensive in vitro and in vivo studies identified compound 2 as a baicalein prodrug candidate that improved the plasma exposure of baicalein in mouse animal studies. Our results demonstrated that this prodrug approach could be further adopted to discover oral baicalein prodrugs.

Highlights

IntroductionBaicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one; Figure 1) is a flavonoid and a major component of Scutellaria baicalensis (S. baicalensis)
Our results demonstrate that this prodrug approach improved the oral absorption of baicalein and may be further adopted to develop oral baicalein prodrugs
Without the protection of the OH groups at the 5- and 6-position, we could selectively conjugate the amino acid with the -OH group at the 7-position of baicalein

Summary

Introduction

Baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one; Figure 1) is a flavonoid and a major component of Scutellaria baicalensis (S. baicalensis). It possesses various beneficial pharmacological activities, including anti-oxidative, anti-proliferative, antiplatelet aggregation, anti-thrombotic, reactive oxygen species (ROS)-scavenging, and anti-angiogenic activities [1,2,3,4,5]. The phase II metabolism of baicalein occurs rapidly during the first-pass in the liver [7]. Baicalein is mainly metabolized to baicalin and baicalein-6-O-glucuronide by uridine diphosphate (UDP)-glucuronosyltransferase in vivo. Baicalin (Figure 1), along with baicalein-7-O-glucuronide, is a key component of S. baicalensis that exhibits antiinflammatory and anti-tumor activities [8,9]. Baicalin is metabolized in vivo to baicalein by the β-glucuronidase [10]

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