Ma Zongchen, Han Xiao, Ren Junde, Liu Kun, Zhang Wenjie, Li Guoqiang
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, P. R. China.
Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266237, P. R. China.
Chem Biodivers. 2023 Feb;20(2):e202201174. doi: 10.1002/cbdv.202201174. Epub 2023 Jan 9.
Guaiazulene and related derivatives were famous for diverse biological activities. In an effort to discover new highly efficient candidate drugs derived from guaiazulene, four series of guaiazulene derivatives were designed, synthesized, and evaluated for antiproliferation, antiviral, anti-inflammatory and peroxisome proliferators-activated receptor γ (PPARγ) signalling pathway agonist activities. Among them, two guaiazulene condensation derivatives showed selective cytotoxic activities towards K562 cell with IC values 5.21 μM and 5.14 μM, respectively, accompanied by slight effects on normal cell viability. For the first time, one guaiazulene derivative from series I exhibited potent antiviral activity towards influenza A virus with IC of 17.5 μM. A guaiazulene-based chalcone showed higher anti-inflammatory activity than positive drug indomethacin with an inhibitory rate of 34.29 % in zebrafish model in vivo. One guaiazulene-based flavonoid could strongly agitate PPARγ pathway at 20 μM, indicating the potential of guaiazulene derivatives to reduce obesity development and ameliorate hepatic steatosis. Preliminary in silico ADME studies predicted the excellent drug-likeness properties of bioactive guaiazulene derivatives.
愈创木薁及其相关衍生物以其多样的生物活性而闻名。为了发现源自愈创木薁的新型高效候选药物，设计、合成了四个系列的愈创木薁衍生物，并对其抗增殖、抗病毒、抗炎和过氧化物酶体增殖物激活受体γ（PPARγ）信号通路激动剂活性进行了评估。其中，两种愈创木薁缩合衍生物对K562细胞表现出选择性细胞毒性活性，IC值分别为5.21 μM和5.14 μM，同时对正常细胞活力有轻微影响。首次，系列I中的一种愈创木薁衍生物对甲型流感病毒表现出强效抗病毒活性，IC为17.5 μM。一种基于愈创木薁的查耳酮在体内斑马鱼模型中显示出比阳性药物吲哚美辛更高的抗炎活性，抑制率为34.29%。一种基于愈创木薁的黄酮在20 μM时可强烈激活PPARγ通路，表明愈创木薁衍生物具有降低肥胖发展和改善肝脂肪变性的潜力。初步的计算机辅助药物代谢动力学（ADME）研究预测了生物活性愈创木薁衍生物具有优异的类药性质。
