Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.ejmech.2019.04.023
Title: The identification of naturally occurring labdane diterpenoid calcaratarin D as a potential anti-inflammatory agent
Authors: Tran, Quy TN 
Wong, WS Fred 
Chai, Christina LL 
Keywords: Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
Labdane-type diterpene
Nuclear factor kappa B
Anti-inflammatory activity
BIOLOGICAL-ACTIVITY
INFLAMMATION
RHIZOMES
ANDROGRAPHOLIDE
ANALOGS
Issue Date: 15-Jul-2019
Publisher: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Citation: Tran, Quy TN, Wong, WS Fred, Chai, Christina LL (2019-07-15). The identification of naturally occurring labdane diterpenoid calcaratarin D as a potential anti-inflammatory agent. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 174 : 33-44. ScholarBank@NUS Repository. https://doi.org/10.1016/j.ejmech.2019.04.023
Abstract: In this study we report, for the first time, the synthesis of the natural product calcaratarin D via a stereo- and regio-selective aldol condensation with (S)-β-hydroxy-γ-butyrolactone as key steps. A concise synthetic route (under 10 steps) to a series of structurally related normal-labdane diterpenes was also developed and their anti-inflammatory activities were evaluated in an in vitro model of inflammation. The structure-activity relationships (SARs) pertaining to the labdane scaffold were elucidated and results suggest that an α-alkylidene-β-hydroxy-γ-butyrolactone system is necessary for potent activity in the labdanes. Our studies identified the natural product calcaratarin D (1) as a promising anti-inflammatory agent, which effectively modulates the production of pro-inflammatory mediators (e.g., TNF-α, IL-6, NO) at both transcriptional and translational levels. These inhibitory effects are likely to occur via the suppression of nuclear factor kappa B (NF-κB) activation by reducing the p65 nuclear translocation but not its phosphorylation or protein expression. Calcaratarin D exhibited significantly greater inhibition of NF-κB activation than andrographolide, a well-known NF-κB inhibitor from the labdane family, suggesting that a normal-configuration labdane ring or the absence of hydroxyl groups at C-3 and C-19 positions is favorable for potent NF-κB inhibition. We further investigated the effects of calcaratarin D on the upstream signalling pathways and found that the compound selectively suppressed the LPS-induced activation of PI3K/Akt pathway without affecting much of the MAPK (i.e., ERK, JNK, and p38) activation. These findings demonstrate that calcaratarin D exerts its anti-inflammatory effects via a selective Akt-NF-κB-mediated mechanism and potentially offers a new therapeutic strategy for the management of inflammatory diseases.
Source Title: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
URI: https://scholarbank.nus.edu.sg/handle/10635/229076
ISSN: 02235234
17683254
DOI: 10.1016/j.ejmech.2019.04.023
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