Specificity and Inhibitory Mechanism of Andrographolide and Its Analogues as Antiasthma Agents on NF-κB p50 (original) (raw)
Related papers
British Journal of Pharmacology, 2005
1 Andrographolide, the major active component from Andrographis paniculata, has shown to possess anti-inflammatory activity. Andrographolide inhibits the expression of several proinflammatory proteins that exhibit a nuclear factor kappa B (NF-kB) binding site in their gene. 2 In the present study, we analyzed the effect of andrographolide on the activation of NF-kB induced by platelet-activating factor (PAF) and N-formyl-methionyl-leucyl-phenylalanine (fMLP) in HL-60 cells differentiated to neutrophils. 3 PAF (100 nM) and fMLP (100 nM) induced activation of NF-kB as determined by degradation of inhibitory factor B a (IkBa) using Western blotting in cytosolic extracts and by binding to DNA using electrophoretic mobility shift assay (EMSA) in nuclear extracts. 4 Andrographolide (5 and 50 mM) inhibited the NF-kB-luciferase activity induced by PAF. However, andrographolide did not reduce phosphorylation of p38 MAPK or ERK1/2 and did not change IkBa degradation induced by PAF and fMLP. 5 Andrographolide reduced the DNA binding of NF-kB in whole cells and in nuclear extracts induced by PAF and fMLP. 6 Andrographolide reduced cyclooxygenase-2 (COX-2) expression induced by PAF and fMLP in HL-60/neutrophils. 7 It is concluded that andrographolide exerts its anti-inflammatory effects by inhibiting NF-kB binding to DNA, and thus reducing the expression of proinflammatory proteins, such as COX-2.
Semisynthesis and cytotoxic activities of andrographolide analogues
Journal of Enzyme Inhibition and Medicinal Chemistry, 2006
Andrographolide 1, a diterpenoid lactone of the plant Andrographis paniculata, known to possess antitumour activity in in vitro and in vivo breast cancer models was subjected to semisynthesis leading to the preparation of a number of novel compounds. These compounds exhibited in vitro antitumour activity with moderate to excellent growth inhibition against MCF-7 (breast) and HCT-116 (colon) cancer cells. Compounds 3,19-(2-chlorobenzylidene)andrographolide(5), 3,19-(3-chlorobenzylidene)andrographolide(6), 3,19-(3-fluorobenzylidene)andrographolide(7), 3,19-(4-fluorobenzylidene)andrographolide(8), 3,19-(2-fluorobenzylidene)andrographolide(10), 3,19-(2-chloro-5-nitrobenzylidene)andrographolide (21), 3,19-(4-chlorobenzylidene)andrographolide(30) and 3,19-(2-chloro-4-fluorobenzylidene) andrographolide(31) were also screened against 60 NCI (National Cancer Institute, USA) human tumour cell lines derived from nine cancer cell types.
Design of 2-Cyclopentenone Derivatives With Enhanced NF-[Kappa] B: DNA Binding Inhibitory Properties
Journal of Molecular …, 2004
In this work we derived a series of new inhibitors for the association between nuclear factor kappa B (NF-kB) and the corresponding kB site in DNA. They were derived through optimization of the lead compound 2-cyclopentenone (CP), which corresponds to the reactive unit of natural product 15-Deoxy-D 12,14 -prostaglandin J 2 (PGJ2). Both CP and PGJ2 possess demonstrated inhibitory efficiency for this and other biological important systems.
Structure Modification of Andrographolide to Improve Its Potency as Anticancer
Indonesian Journal of Chemistry, 2010
Andrographolide, a diterpenoid lactone isolated from the herb of Andrographis paniculata and known to possess antitumor activity in breast cancer models was subjected to semisynthesis leading to the preparation of a number of derivatives. After protection of the two hydroxyl groups present at C-3 and C-19 to give 3,19-isopropylidene and 3,19-benzylidene andrographolides, the remaining hydroxyl group at C-14 of andrographolide was treated with acid anhydride or acid chloride under base condition. Unfortunately, the reactions gave only 14-dehydroandrographolide as well as unidentified diacyl compounds in replace of the target molecule 14-O-acyl andrographolide. An alternative procedure using neat acetic anhydride under reflux gave the acetyl derivatives. The resulted compounds exhibited cytotoxic activity against MCF-7 breast cancer cells with better growth inhibition than the parent compound andrographolide. Keywords: andrographolide, acylation, anticancer, cytotoxic, breast cancer...
PLOS ONE, 2015
The nuclear factor κB (NF-κB) is a promising target for drug discovery. NF-κB is a heterodimeric complex of RelA and p50 subunits that interact with the DNA, regulating the expression of several genes; its dysregulation can trigger diverse diseases including inflammation, immunodeficiency, and cancer. There is some experimental evidence, based on whole cells studies, that natural sesquiterpene lactones (Sls) can inhibit the interaction of NF-κB with DNA, by alkylating the RelA subunit via a Michael addition. In the present work, 28 natural and semisynthetic pseudoguianolides were screened as potential inhibitors of NF-κB in a biochemical assay that was designed using pure NF-κB heterodimer, pseudoguianolides and a~1000 bp palindromic DNA fragment harboring two NF-κB recognition sequences. By comparing the relative amount of free DNA fragment to the NF-κB-DNA complex, in a routine agarose gel electrophoresis, the destabilizing effect of a compound on the complex is estimated. The results of the assay and the following structure-activity relationship study, allowed the identification of several relevant structural features in the pseudoguaianolide skeleton, which are necessary to enhance the dissociating capacity of NF-κB-DNA complex. The most active compounds are substituted at C-3 (α-carbonyl), in addition to having the α-methylene-γ-lactone moiety which is essential for the alkylation of RelA.
Docking studies of andrographolide and its In vitro validation
International Journal of Chemical Studies, 2018
In silico molecular docking is one of the most popular molecular modeling approach, used to predict binding poses of ligands to target proteins (TP). It can be used to predict the affinity of ligands to TP. Andrographolide, a biomolecule of plant Andrographis paniculata, with medicinal property will be studied for finding interaction with TP (diseased proteins of human and plant origin). Nine different target proteins HIV protease, THNR reductase, trichothecene-3-O-acetyl transferase, cyclooxygenase, acetylcholine esterase, polygalacturonase, glucosamine-6-phosphate synthase, phosphoshikimate transferase and N-acetyl-β-D-hexosaminidase will be docked with andrographolide using Argus 4.0 bioinformatics software. After successful docking in vitro validation of andrographolide activity will be checked by subjecting S.rolfsii, R.solani and F.udum fungus disease causing agents of tomato with Andrographis extract and efficacy will be evaluated. These results anticipate the application of ...
ITB Journal of …, 2009
Cyclooxygenase (COX), an enzyme involved in the conversion of arachidonic acid to prostaglandins, exists in two isoforms, which are COX-1 and COX-2. Despite the similarities of COX-1 and COX-2, the two isoforms show subtle differences in amino acid composition at the active sites. Since COX-1 has isoleucine, a bulkier amino acid at position 523 than COX-2's valine, it allows COX-2 to have a larger space in its active site. Andrographolide reduces COX-2 expression induced by PAF and fMLP in HL60/neutrophils. Neoandrographolide inhibits COX-2 expression at the translational level. The purpose of this study is to examine the binding modes of andrographolide and neoandrographolide against COX-1 and COX-2 in terms of hydrogen bonds and docking energy, to understand their antiinflammatory property. The docking simulation indicates that both andrographolide and neoandrographolide are able to be located in the COX-2's binding pocket but not in the COX-1's. It confirms that COX-1's binding pocket is smaller than COX-2's. Based on this study, both andrographolide and neoandrographolide show selective inhibitory property to COX-2. Their selectivity are due to their specific interaction with Arg 513 in the binding pocket of COX-2, which is also shown by SC-558, a COX-2 selective inhibitor.