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.
Highlights
The use of natural products as scaffolds for the generation of chemically diverse screening libraries is one of the effective methods for drugs screening[1]
The EtOAc-soluble fraction of the ethanolic extract of the dried flowers of I. britannica was repeatedly passed through column chromatography, followed by purification by preparative TLC to afford 1β-hydroxy alantolactone (1) and ivangustin (2) in previous papers by others and us[3,22,35]
When 2 equivalent of KOAc was added in the reaction solution, TLC detection for the reaction showed the complete consumption of the starting material, and the spirobislactone 1j was given in 76% yield
Summary
The use of natural products as scaffolds for the generation of chemically diverse screening libraries is one of the effective methods for drugs screening[1]. The two compounds containing α-methylene-γ-lactone moiety have several biological effects, including anti-tumor and anti-inflammation activity[3,22]. Reported synthetic modifications to STLs resulted in variation of anticancer activity, including esterification and oxidation of hydroxyl group (–OH), reduction, amination and coupling reaction of α-methylene-γ-lactone motif and cyclopropanation of double bond[19,27,28,29,30,31,32]. In our ongoing endeavor on enriching chemical diversity of the STLs molecular framework to discover pharmacologically interesting compounds, in this study, we prepared a series of new derivatives of 1 and 2 through esterification, oxidation, reduction and [3 + 2] reactions at their C1 or C13 positions. The most active compound 1i was selected for further experiments and to determine its mechanistic basis of action in the PC-3 cell line
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