Design and synthesis of guaianolide-germacranolide heterodimers as novel anticancer agents against hepatocellular carcinoma

doi:10.1002/ddr.22087

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	Design and synthesis of guaianolide-germacranolide heterodimers as novel anticancer agents against hepatocellular carcinoma
	Yan,Jia-Xin; Li,Qi-Hao; Li,Tian-Ze; Huang,Zhi-Yan; Ma,Yun-Bao; Chen,Ji-Jun
	2023
发表期刊	DRUG DEVELOPMENT RESEARCH
ISSN	1098-2299
摘要	Inspired by our previous finding that disesquiterpenoids showed more potent antihepatoma cytotoxicity than their corresponding parent monomers, natural product-like guaianolide-germacranolide heterodimers were designed and synthesized from guaianolide diene and germacranolides via a biomimetic Diels-Alder reaction to provide three antihepatoma active dimers with novel scaffolds. To explore the structure-activity relationship, 31 derivatives containing ester, carbamate, ether, urea, amide, and triazole functional groups at C-14 & PRIME; were synthesized and evaluated for their cytotoxic activities against HepG2, Huh7, and SK-Hep-1 cell lines. Among them, 25 compounds were more potent than sorafenib against HepG2 cells, 15 compounds were stronger than sorafenib against Huh7 cells, and 17 compounds were stronger than sorafenib against SK-Hep-1 cells. Compound 23 showed the most potent cytotoxicity against three hepatoma cell lines with IC50 values of 4.4 & mu;M (HepG2), 3.7 & mu;M (Huh7), and 3.1 & mu;M (SK-Hep-1), which were 2.7-, 2.2-, and 2.8-fold more potent than sorafenib, respectively. The underlying mechanism study demonstrated that compound 23 could induce cell apoptosis, prevent cell migration and invasion, cause G2/M phase arrest in SK-Hep-1 cells. Network pharmacology analyses predicted PDGFRA was one of the potential targets of compound 23, and surface plasmon resonance (SPR) assay verified that 23 had strong affinity with PDGFRA with a dissociatin constant (KD) value of 90.2 nM. These promising findings revealed that structurally novel guaianolide-germacranolide heterodimers might provide a new inspiration for the discovery of antihepatoma agents.
关键词	antihepatoma effects guaianolide-germacranolide heterodimers PDGFRA DERIVATIVES
学科领域	Pharmacology & Pharmacy
DOI	10.1002/ddr.22087
收录类别	SCI
WOS记录号	WOS:001013790700001
引用统计	被引频次：1[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75318
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Yan,Jia-Xin,Li,Qi-Hao,Li,Tian-Ze,et al. Design and synthesis of guaianolide-germacranolide heterodimers as novel anticancer agents against hepatocellular carcinoma[J]. DRUG DEVELOPMENT RESEARCH,2023.
APA	Yan,Jia-Xin,Li,Qi-Hao,Li,Tian-Ze,Huang,Zhi-Yan,Ma,Yun-Bao,&Chen,Ji-Jun.(2023).Design and synthesis of guaianolide-germacranolide heterodimers as novel anticancer agents against hepatocellular carcinoma.DRUG DEVELOPMENT RESEARCH.
MLA	Yan,Jia-Xin,et al."Design and synthesis of guaianolide-germacranolide heterodimers as novel anticancer agents against hepatocellular carcinoma".DRUG DEVELOPMENT RESEARCH (2023).

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