Synthesis and structure–activity relationships of guaiane-type sesquiterpene lactone derivatives with respect to inhibiting NO production in lipopolysaccharide-induced RAW 264.7 macrophages

Chen, Hao; Chen, Bingyang; Liu, Chun‐Ting; Zhao, Zichen; Shao, Wen‐Hao; Yuan, Haichao; Bi, Kaijian; Liu, Jiang-Yun; Sun, Qian; Zhang, Weidong

doi:10.1016/j.ejmech.2014.06.043

Cited by 16 publications

(7 citation statements)

References 25 publications

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“…In this route, the important intermediate compound 2 was first synthesized based on our previous study. 38 Compound 2 was then treated with tbutyldimethylsilyl triflate (TBSOTf) to protect the 2-hydroxyl group and obtain compound 3. To form compound 5, a twostep procedure of selective dehydrogenation of the α-methyl-γlactone moiety was used that included the formation of phenylseleno-substituted 4 followed by treatment with hydrogen peroxide (H 2 O 2 ).…”

Section: ■ Chemistrymentioning

confidence: 99%

Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α-Santonin Derivatives

Chen

Gao

et al. 2017

J. Med. Chem.

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As a therapeutic target for antitumor necrosis factor (TNF)-α interventions, UbcH5c is one of the key ubiquitin-conjugating enzymes catalyzing ubiquitination during TNF-α-triggered nuclear factor kappa B (NF-κB) activation. In the present study, three series of analogues were designed and synthesized from α-santonin, and their UbcH5c inhibitory activities were screened by Western blotting and NF-κB luciferase assay. Further BIAcore, in-gel fluorescence imaging, and immunoprecipitation assays demonstrated that compound 6d exhibited robust and specific inhibition of UbcH5c, exceeding that of the positive compound 1 (IJ-5). Mechanistic investigations revealed that compound 6d preferentially bound to and inactivated UbcH5c by forming a covalent adduct with its active site Cys85. Furthermore, compound 6d exhibited potent anti-inflammatory activity against complete Freund's adjuvant-induced adjuvant arthritis in vivo. These findings suggest that the novel α-santonin-derived UbcH5c inhibitor 6d is a promising lead compound for the development of new antirheumatoid arthritis (RA) agent.

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Section: ■ Chemistrymentioning

confidence: 99%

Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α-Santonin Derivatives

Chen

Gao

et al. 2017

J. Med. Chem.

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“…Guaianes have been reported to have significant cytotoxic, , anti-inflammatory, antibacterial, antimalarial, and antidepressant properties . Owing to their intriguing structures with a large substitution diversity and impressive bioactivity, many chemists and pharmacologists have focused on the synthesis, biotransformation, and structure–activity relationships of guaiane analogues. − However, most guaianes contain multiple stereogenic centers. The absolute configurations of many guaianes, such as xylaguaianols A–D, 4,10-epizedoarondiol, 15-hydroxyprocurcumenol, 12-hydroxycurcumenol, (1β,5β)-1-hydroxyguaia-4(15),11(13)-diene-12,5-lactone, 1,5-epoxy-4-hydroxyguai-11(13)-en-12-oic acid, 2α,4α-dihydroxy-1β-guai-11(13),10(14)-dien-12,8α-olide, 5α,6α-epoxy-2α,4α-dihydroxy-1β-guai-11(13)-en-12,8α-olide, and 6α-hydroxyinuchinenolide B, have not yet been determined.…”

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confidence: 99%

Absolute Configurations and Bioactivities of Guaiane-Type Sesquiterpenoids Isolated from Pogostemon cablin

Zhou

Chen

et al. 2018

J. Nat. Prod.

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Seven novel guaiane sesquiterpenoids (1-7) and three known seco-guaianes were isolated from the volatile oil of Pogostemon cablin. Their structures including absolute configurations were determined by spectroscopic analyses, a modified Mosher's method, and X-ray diffraction and ECD data. The results indicated that the ECD Cotton effects arising from one or two nonconjugated olefinic chromophores could be applied to define the absolute configurations of guaiane sesquiterpenoids. Compounds 3 and 6 exhibited significant vasorelaxant activity against phenylephrine-induced and KCl-induced contractions of rat aorta rings [half-maximal effective concentration (EC) of 3 against PHE-induced contraction, 5.4 μM; EC of 6 against PHE- and KCl-induced contractions, 1.6 and 24.2 μM, respectively]. They also showed antifungal activity against Candida albicans (minimum inhibitory concentrations, 500 and 300 μM, respectively). In addition, 2 and 7-9 displayed a neuroprotective effect against glutamate-induced injury in PC12 cells.

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“…Inhibition of 5-lipoxygenase has been reported for some santonin derivatives (Schwarz et al., 2007). Santonin and its analogues also inhibit macrophage nitric oxide synthase (Chen et al., 2014), which is involved in inflammation. Moreover, a synthesis of leucodin from santonin has been reported (White et al., 1969), thus it seemed a great shortcut to get the so precious pseudoguaianolide.…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring sesquiterpene lactones and their semi-synthetic derivatives modulate PGE2 levels by decreasing COX2 activity and expression

Perri

Frattaruolo

Haworth³

et al. 2019

Heliyon

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Plants of the Asteraceae family have been used in traditional medicine for centuries due to their main antimicrobial and analgesic activities. A liniment from Artemisia californica has recently been tested on patients affected by either acute pain or chronic pain conditions with great success. The aim of this study was to evaluate the anti-inflammatory activity of sesquiterpene lactones (SLs), representing the majority in the Asteraceae family. Leucodin, α-santonin and sclareolide (three SLs) were chosen to undergo chemical modifications. This pool of molecules underwent molecular modeling experiments using an in-house program, WATGEN, predicting the water network and its contribution to the overall affinity of the enzyme-ligand complex. The anti-inflammatory activity and the ability of compounds to modulate COX-2 expression have been evaluated in LPS-stimulated RAW 264.7 cells and in RIF-1 cells treated according to the Photodynamic Therapy (PDT) protocols using Photoprin (PH) as photosensitizer. Furthermore, commercially available assay kits were used to evaluate the concentration of PGE-2 and the direct inhibition of COX-2. All the tested molecules fit well in the enzyme binding pocket, but to get a substantial inhibition of the expression and activity of the enzyme as well as a reduction in the PGE2 concentration, high concentrations of the compounds are needed. The only exceptions being leucodin itself and FP6 , one of the α-santonin derivatives, presenting a CF 3 functional group. We believe that this class of compounds has some interesting potential in the treatment of pain and inflammation. Although, the activity seems to be due to a mechanism related to the expression of the COX enzymes rather than on a direct inhibition.

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Synthesis and structure–activity relationships of guaiane-type sesquiterpene lactone derivatives with respect to inhibiting NO production in lipopolysaccharide-induced RAW 264.7 macrophages

Cited by 16 publications

References 25 publications

Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α-Santonin Derivatives

Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α-Santonin Derivatives

Absolute Configurations and Bioactivities of Guaiane-Type Sesquiterpenoids Isolated from Pogostemon cablin

Naturally occurring sesquiterpene lactones and their semi-synthetic derivatives modulate PGE2 levels by decreasing COX2 activity and expression

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