Affiliation:
1. School of Traditional Chinese Materia Medica Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning province Key Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang City Shenyang Pharmaceutical University Shenyang 110016 P.R. China
2. School of Pharmaceutical Engineering Shenyang Pharmaceutical University Shenyang 110016 P.R. China
Abstract
AbstractIn this study, a visible‐light‐induced intermolecular [2+2] photocycloaddition reaction based on flavonoids was constructed to address the problems of low yield, poor physicochemical properties, and lack of target definition in total synthesis of (±)‐millpuline A whose bioactivity remains unknown. As a result, 20 derivatives were synthesized for bioactivity evaluation. Consequently, lung cell protective effects of (±)‐millpuline A and compound B13 a were revealed for the first time and the crucial role of stereoconfiguration of the cyclobutane moiety in their protective effects against NNK in normal lung cells was demonstrated. Moreover, through target prediction and experimental verification in MLE‐12 cells, SRC was determined to be the target of (±)‐millpuline A regarding its protective effect in NNK‐induced lung cell injury. Results from RT‐Q‐PCR and HTRF experiments verified that (±)‐millpuline A could repress SRC activity through a transcriptional mechanism but not acting as an inhibitor to directly bind to and thereby inhibit SRC protein. The results in this paper are informative for the further development of visible light‐catalyzed cycloaddition of flavonoids and lay a scientific foundation for understanding the bioactivity and underlying mechanism of (±)‐millpuline A and other structurally similar natural skeletons.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Liaoning Province
Subject
Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology