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  2. Diversity Modification and Structure-Activity Relationships of Two Natural Products 1β-hydroxy Alantolactone and Ivangustin as Potent Cytotoxic Agents

Diversity Modification and Structure-Activity Relationships of Two Natural Products 1β-hydroxy Alantolactone and Ivangustin as Potent Cytotoxic Agents

  • Sci Rep. 2018 Jan 29;8(1):1722. doi: 10.1038/s41598-018-20192-9.
Jiang-Jiang Tang 1 Qiu-Rui He 2 Shuai Dong 2 Xin Guo 2 Yu-Gong Wang 2 Bei-Lei Lei 3 Jun-Mian Tian 2 Jin-Ming Gao 4
Affiliations

Affiliations

  • 1 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, China. tangjiang11@nwsuaf.edu.cn.
  • 2 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, China.
  • 3 College of Life Sciences, Northwest A&F University, Yangling, 712100, China.
  • 4 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, China. jinminggao@nwsuaf.edu.cn.
Abstract

Sesquiterpene lactones (STLs) are a class of plant secondary metabolites widely found in nature with potent antitumor activities. In this work, two isolated STLs 1β-hydroxy alantolactone (1) and ivangustin (2) were derivatized through diversity-oriented strategy, and in vitro cytotoxic activity assessments were conducted against six cell lines including HeLa, PC-3, HEp-2, HepG2, CHO and HUVEC. The cytotoxic structure-activity relationship showed that the double bond between C5 and C6 was beneficial to improve activity; C1-OH oxidized derivatives showed a slight stronger activity, comparable to the positive drug etoposide (VP-16). Yet, C1-OH esterified derivatives decreased the potency which were different from those of 1-O-acetylbritannilactone (ABL) reported previously by us, and C13-methylene reductive and spiro derivatives resulted in almost complete ablation of cytotoxic activity. Mechanistic basis of cytotoxicity of the representative compound 1i was assayed to relate with Apoptosis and cell cycle arrest. Furthermore, 1i inhibited TNF-α-induced canonical NF-κB signaling in PC-3 cells. Molecular modeling studies exhibited additional hydrogen bond interaction between 1i and the residue Lys37 of p65, indicating that 1i could form covalent protein adducts with Cys38 on p65.

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