Protostane Triterpenoids from the Rhizome of<i> Alisma orientale</i> Exhibit Inhibitory Effects on Human Carboxylesterase 2

Mai, Zhen-Peng; Zhou, Kun; Ge, Guang-Bo; Wang, Chao; Huo, Xiaokui; Dong, Peipei; Deng, Sa; Zhang, Baojing; Zhang, Hou-Li; Huang, Shanshan; Ma, Xiaochi

doi:10.1021/acs.jnatprod.5b00321

Cited by 71 publications

(37 citation statements)

References 35 publications

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“…Two pentacyclic triterpenoids, ursolic acid (UA) and oleanolic acid (OA), exhibited strong inhibitory effects on CES1 ( Fig. 6 ) 97 , 98 , 99 , 100 . By structural modifications on OA and UA, two derivatives including 3 β - O -( β -carboxy-propionyl)-urs-12-en-28-oic acid and 3 β - O -( β -carboxypropionyl)-olean-12-en-28-oic acid were obtained, which displayed very strong inhibitory effects against CES1 ( K i value as 0.012 µmol/L and 0.017 µmol/L, respectively) and high selectivity over CES2 (6919-fold and 3296-fold against CES2, respectively).…”

Section: Ces Inhibitorsmentioning

confidence: 99%

“…This compound showed high selectivity over CES1 (>1000-fold), which is 3463-fold more potent than the parent compound GA. Recently, 22 protostane triterpenoids have been isolated from the rhizome of Alismaorientale 99 . Among them, five could potently inhibit CES2, with IC 50 values less than 10 µmol/L.…”

Section: Ces Inhibitorsmentioning

confidence: 99%

“…Among them, five compounds, including alismanol H, 25- O -butyl alisol A, alisol A 23,24-acetonide, 24-deacetyl alisol O, 16,23-oxido alisol B displayed strong inhibitofry effects on CES2, with the IC 50 values less than 3.0 µmol/L ( Fig. 6 ) 97 , 98 , 99 , 100 , 101 .

Figure 6 Triterpenoids as inhibitors of CES.…”

Section: Ces Inhibitorsmentioning

confidence: 99%

“…Recent research has revealed that some natural flavonoids are strong inhibitor against both CES1 and CES2 ( Fig. 7 ) 98 , 99 , 100 . Bavachinin and corylin significantly inhibited the CES1-mediated BMBT hydrolysis with low K i values as 0.5 µmol/L and 0.7 µmol/L, respectively, while corylifol A found in Fructus Psoraleae (also named Bu-gui-shi), is a potent inhibitor against CES2 with the K i value of 0.62 μmol/L 100 , 101 , 104 , 105 , 106 .…”

Section: Ces Inhibitorsmentioning

confidence: 99%

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Human carboxylesterases: a comprehensive review

Wang

Zou

Jin

et al. 2018

Acta Pharmaceutica Sinica B

358

268

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Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.

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Section: Ces Inhibitorsmentioning

confidence: 99%

Section: Ces Inhibitorsmentioning

confidence: 99%

Figure 6 Triterpenoids as inhibitors of CES.…”

Section: Ces Inhibitorsmentioning

confidence: 99%

Section: Ces Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Human carboxylesterases: a comprehensive review

Wang

Zou

Jin

et al. 2018

Acta Pharmaceutica Sinica B

358

268

View full text Add to dashboard Cite

show abstract

“…To data, many phytochemicals including flavonoids (Li et al, 2015; Sun et al, 2016), tanshinones (Hatfield et al, 2013), and triterpenoids (Mai et al, 2015; Zou et al, 2016) have been reported with inhibitory effects against human carboxylesterases. However, most of these natural compounds demonstrated more potent inhibitory effects against hCE2 in contrast to hCE1 (Hatfield and Potter, 2011; Umehara et al, 2016; Xu et al, 2016; Wang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1

et al. 2017

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Human carboxylesterase 1 (hCE1), one of the most important serine hydrolases distributed in liver and adipocytes, plays key roles in endobiotic homeostasis and xenobiotic metabolism. This study aimed to find potent and selective inhibitors against hCE1 from phytochemicals and their derivatives. To this end, a series of natural triterpenoids were collected and their inhibitory effects against human carboxylesterases (hCEs) were assayed using D-Luciferin methyl ester (DME) and 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB) as specific optical substrate for hCE1, and hCE2, respectively. Following screening of a series of natural triterpenoids, oleanolic acid (OA), and ursolic acid (UA) were found with strong inhibitory effects on hCE1 and relative high selectivity over hCE2. In order to get the highly selective and potent inhibitors of hCE1, a series of OA and UA derivatives were synthesized from OA and UA by chemical modifications including oxidation, reduction, esterification, and amidation. The inhibitory effects of these derivatives on hCEs were assayed and the structure-activity relationships of tested triterpenoids as hCE1 inhibitors were carefully investigated. The results demonstrated that the carbonyl group at the C-28 site is essential for hCE1 inhibition, the modifications of OA or UA at this site including esters, amides and alcohols are unbeneficial for hCE1 inhibition. In contrast, the structural modifications on OA and UA at other sites, such as converting the C-3 hydroxy group to 3-O-β-carboxypropionyl (compounds 20 and 22), led to a dramatically increase of the inhibitory effects against hCE1 and very high selectivity over hCE2. 3D-QSAR analysis of all tested triterpenoids including OA and UA derivatives provide new insights into the fine relationships linking between the inhibitory effects on hCE1 and the steric-electrostatic properties of triterpenoids. Furthermore, both inhibition kinetic analyses and docking simulations demonstrated that compound 22 was a potent competitive inhibitor against hCE1-mediated DME hydrolysis. All these findings are very helpful for medicinal chemists to design and develop highly selective and more potent hCE1 inhibitors for biomedical applications.

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Evidence for Shikonin acting as an active inhibitor of human carboxylesterases 2: Implications for herb–drug combination

Cao

et al. 2018

Phytotherapy Research

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Shikonin, a natural naphthoquinone compound derived from the herb Lithospermum erythrorhizon, is widely used for its various pharmacological activities. However, its potential interactions with other medications by inhibiting human carboxylesterases 2 (hCE2) remain unknown. In this study, the inhibitory effects of shikonin on the activity of hCE2 in human liver microsomes are investigated by using fluorescein diacetate (FD), N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN), and CPT-11 as substrates of hCE2. The results demonstrate that shikonin significantly inhibits the activity of hCE2 when FD and NCEN are used as substrates, whereas the half inhibition concentration value of shikonin increased by 5-30 times when CPT-11 was used as the substrate. The inhibition types of shikonin against hCE2 activity reflected by 3 substrates were all best fit to noncompetitive manners. In addition, shikonin was found to distinctly suppress endogenous hCE2 activity, characterized with attenuated fluorescence. Furthermore, for drugs metabolized by hCE2 with the similar binding sites with FD or NCEN, the estimated magnitudes of area under the curve variation were approximately 9-357% in the presence of shikonin. Also, the area under the curve of CPT-11 could be increased by 1-14% following administration of shikonin. These findings have clear clinical implications for the combination of shikonin and hCE2-metabolizing prodrugs.

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Protostane Triterpenoids from the Rhizome of Alisma orientale Exhibit Inhibitory Effects on Human Carboxylesterase 2

Cited by 71 publications

References 35 publications

Human carboxylesterases: a comprehensive review

Human carboxylesterases: a comprehensive review

Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1

Evidence for Shikonin acting as an active inhibitor of human carboxylesterases 2: Implications for herb–drug combination

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