Semisynthesis, an Anti-Inflammatory Effect of Derivatives of 1β-Hydroxy Alantolactone from Inula britannica

Abstract

1β-hydroxy alantolactone, a sesquiterpene lactone mainly isolated from Inula genus plants, exhibits potent anti-inflammatory and anticancer activities. In this work, 1β-hydroxy alantolactone was isolated and five derivatives were prepared through different reactions at the C1-OH and C13-methylene motifs. The structure–activity relationships (SAR) of anti-inflammatory effects against NO production in RAW264.7 cells showed that the α-methylene-γ-butyrolactone motif was essential for NO production suppression and that retaining the C1-OH group can remarkably improve this effect. The NF-κB signaling pathway plays a pivotal role in the regulation of NO expression. Moreover, the levels of p65 and p50 phosphorylation were investigated and active compound 1 inhibited phosphorylation of p65 and p50 in TNF-α-induced NF-κB signaling. Further molecular docking suggested that 1 may target the p65 of NF-κB.

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

“…As illustrated in Fig. 2 , 1 and 2 were converted to the corresponding ester derivatives 1a – h and 2a – c with aliphatic chain and aromatic moieties using different anhydrides or benzoyl chloride or cinnamic acid 34 . Geometric structure of the derivative 1a was further verified by X-ray crystallography (Fig.…”

“…3 ). Oxidation of C1-OH of compounds 1 and 2 was carried out with mild oxidant Dess-Martin periodinane (DMP) to afford 1i 34 and 2d (Fig. 2 ).…”

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Figure 2 Synthesis of C1-OH modified derivatives of 1β-hydroxy alantolactone ( 1 ) and ivangustin ( 2 ). Conditions and reagents: ( a ) anhydride, Et 3 N, DMAP, rt, for 1a , 1b , 1h and 2a , 2b ; benzoyl chloride, pyridine, 0 °C for 1c , 1e , 1d and 2c ; cinnamic acid, DMAP, DCC, 60 °C for 1f , 1g and 2d ; 30 min–8 h, 45–90%; ( b ) Dess-Martin periodinane (DMP), CH 2 Cl 2 , rt, 85% for 1i 34 , 76% for 2d .

Figure 3 The X-ray crystal structure of 1a (CCDC: 1504780).

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“…Meanwhile, another spirobicyclic derivatives 1k – q were prepared via 1,3-dipolar cycloaddition of 1i 34 . As described in Fig.…”

“…We have found that 1- O -acetyl-6- O -lauroylbritannilactone (ABL-L), an esterified derivative of 1- O -acetylbritannilactone (ABL), showed 4–10 fold stronger suppression against cancer cells by inducing apoptosis via a p53-dependent pathway 19 , 33 . 1β-Hydroxy alantolactone ( 1 ) retaining C1-OH exhibited stronger anti-inflammatory effect in RAW 264.7 cells 34 . 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.…”