Synthesis of lantadene analogs with marked in vitro inhibition of lung adenocarcinoma and TNF-α induced nuclear factor-kappa B (NF-κB) activation

Monika, .; Sharma, Ankesh; Kumar, Sunita; Aggarwal, Vaibhav; Lee, Hong Boon; Sharma, Manu

doi:10.1016/j.bmcl.2014.06.068

Cited by 13 publications

(6 citation statements)

References 18 publications

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“…Activation of NF-κB in cancer cells is often associated with drug resistance as both radio-and chemo-therapies induce constitutive activation of the NF-κB pathway (43). Therefore, a compound's ability to block the NF-κB pathway is important for the efficacy of cancer therapy (44).…”

Section: Discussionmentioning

confidence: 99%

In vitro antitumor effects of two novel oligostilbenes, cis- and trans-suffruticosol D, isolated from Paeonia suffruticosa seeds

Almosnid

Gao

et al. 2015

International Journal of Oncology

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Abstract. Naturally derived stilbenes have been shown to elicit cytotoxic, anti-steroidal, anti-mutagenic, anti-oxidative, anti-inflammatory, and antitumor bioactivities. Previous phytochemical studies revealed that the seeds of Paeonia suffruticosa are rich in natural stilbenes. In this study the antitumor effects and mechanism of action of the oligostilbene isomers, cis-and trans-suffruticosol D, isolated from the seeds of P. suffruticosa were examined. cis-and transsuffruticosol D exhibited remarkable cytotoxicity against the human cancer cell lines A549 (lung), BT20 (breast), MCF-7 (breast), and U2OS (osteosarcoma), but showed significantly less toxicity to the normal human cell lines HMEC (breast) and HPL1A (lung). We also demonstrated that cis-and transsuffruticosol D exerted their antitumor effects by provoking oxidative stress, stimulating apoptosis, decreasing the mitochondrial membrane potential, inhibiting cell motility, and blocking the NF-κB pathway in human lung cancer cells. In addition, we evaluated their respective bioefficacy and found that trans-suffruticosol D is more potent than cissuffruticosol D. Collectively, our results suggest that cis-and trans-suffruticosol D could be promising chemotherapeutic agents against cancer. IntroductionCurrent cancer medications are costly and often cause serious side effects. The US National Cancer Institute began investigating antitumor plant extracts in the 1960s, and the premise that natural compounds obtained from therapeutic plants could produce anticancer medications has henceforth been of great research interest. Traditional Chinese medicines (TCMs) using dried plants or plant extracts have provided low cost diet and pharmaceutical therapies for thousands of years and experimental and clinical studies have proven that >400 plant species used in TCMs as anticancer herbal medications are significantly effective in the prevention or treatment of various cancers (1-4). However, much work remains to be done to determine the effectiveness of the individual compounds present in the TCMs.Paeonia suffruticosa, or Paeoniaceae, is a widely utilized Chinese medicinal plant within the Paeonia genus. This genus comprises ~35 species that are classified into three groups: Oneapia, Paeonia, and Moutan (5). The Cortex Moutan (root cortex) of Paeonia has been recorded by China's Pharmacopoeia as a significant source of herbal medicine (6). Extracts of Paeonia have been shown to possess cytotoxic, antitumor, anti-inflammatory and anti-oxidative activities (5). Previous photochemical research on Paeonia identified >260 bioactive compounds, including phenols, monoterpenoidglucosides, paeonols, flavonoids, tannins, steroids, triterpenoids and stilbenes (7). A more recent study showed that the seeds of Paeonia contain considerable quantities of stilbenes compared to the other compounds (7,8).Stilbenes are a class of polyphenols widely found in plants that contain a 1.2-diphenylethylene nucleus in their structure (9). Stilbenes have aroused great interest due to their antit...

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Section: Discussionmentioning

confidence: 99%

In vitro antitumor effects of two novel oligostilbenes, cis- and trans-suffruticosol D, isolated from Paeonia suffruticosa seeds

Almosnid

Gao

et al. 2015

International Journal of Oncology

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“…receptor and the TNF receptor to the dead zone, TRAF2 and serine /threonine kinase RIP. In the activated NF-kappa B signal pathway, after IkBα is phosphorylated, the nuclear localization signal on NF-KB is exposed, and NF-kB enters the nucleus from the cytoplasm and binds to the KB site on the regulatory gene promoter to induce the transcription of the target gene, thus inducing a large number of in ammatory cytokines to participate in the in ammatory response [33]. IkBα is a key protein in the NF-kappa B pathway, which is necessary for the activation of NF-KB mediated by TNF-α.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, 33 Screening core targets 3652 targets were retrieved from the GeneCards database, and the data from GSE48060 and GSE66360 chips and platform were downloaded from the GEO database. 898 signi cant differential genes were obtained.…”

Section: Collection Of Clmn Active Ingredients and Targetsmentioning

confidence: 99%

Network Pharmacology to Explore Active Components and Pharmacological Mechanism of Action of Compound Longmai Ning Decoction for the Treatment of Myocardial Infarction

Wang

et al. 2021

Preprint

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Background and objective: Myocardial Infarction (MI) is a cardiovascular disease with a high morbidity and mortality rate. While MI is currently treated with pharmaceuticals, there is a need for new treatment options: compound Chinese medicines may have unique advantages for the treatment of MI. In this study, we used network pharmacology to explore the molecular mechanisms of action of Chinese Longmai Ning decoction (CLMN) as a potential treatment approach.Methods: Chip data related to Myocardial Infarction were downloaded from the GEO database and genes from GSE48060 and GSE66360 chips were obtained by R language. The targets of active components of compound CLMN and myocardial infarction disease were predicted by network pharmacology. After intersection analysis, the core targets were obtained and functional enrichment analysis was carried out. CLMN biological activity was verified by molecular docking prior to establishing a mouse MI model to verify efficacy using hematoxylin-eosin staining (HE) and immunohistochemistry.Results: KEGG pathway analysis showed that TNF, IL1B, PTGS2, VCAM1, and NFKBIA which mainly act on NF-kappa B pathway contribute to the anti-inflammatory effects of CLMN. Immunohistochemical analysis showed that TNF-α and TRAF-2 expression levels in MI of CLMN-treated mice were decreased, while IkBα was increased (P < 0.05). HE staining showed CLMN reduced inflammation in mouse cardiomyocytes and decreased fibrosis.Conclusion: CLMN regulates the NF-kappa B signaling pathway and the expression of TNF, IL1B, PTGS2, VCAM1 and NFKBIA. Chemical analysis showed that CLMN active components such as Daidzein-4,7-diglucoside, rutin and puerarin may be responsible for the therapeutic effect of the decoction.

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“…We have chosen the dataset of recently synthesised and evaluated Lantadenes (1-4) and their modified analogues (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) from the published report as indicated in Figure 1. 21…”

Section: Datasetmentioning

confidence: 99%

“…These analogues displayed significant antiproliferative activity and provided us with 10 and 12 as promising candidates against lung cancer. 21 In silico based virtual screening have become an integral part of academic and industrial research. One of the technique like molecular docking has been extensively used in last two decades for macromolecular targets identifications, prediction of binding affinity and activity of the molecules.…”

Section: Introductionmentioning

confidence: 99%

Lantadenes Targeting NF-ΚB in Cancer: Molecular Docking and ADMET Predictions

Sharma

Aggarwal

et al. 2021

Int J Life Sci Pharm Res

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Natural products and their scaffolds encompasses an array of molecular entities as starting points for drug designing and discovery. In the past two decades, phytochemically driven Lantadenes and their modified analogues have attracted lots of attention due to their tumor necrosis factor-α induced nuclear factor-kappa B inhibition and consequently their promising anticancer potential. Earlier reports described the synthesis of esters at C-3 and C-22 of pentacyclic triterpenoid Lantadene, and their evaluation to inhibit tumor necrosis factor-α induced nuclear factor-kappa B along with cytotoxicity against A549 lung cancer cells. In the modern drug discovery process, molecular docking have become an integral part of drug design. Combination of computational platforms and experimental strategies have allowed many successful stories in the discovery of new structure-based or mechanism drugs. Thus as a continuation of our research concerning Lantadenes and their significance, present study has been undertaken to predict binding mode, pharmacokinetic and drug likeness using Vlife MDS Biopredicta and ADMETlab tools. In silico inspired grip docking approach was utilized to estimate binding interactions of all the optimized Lantadenes and their modified ester against nuclear factor-kappa B receptor (PDB ID: 1LE9). In addition, all the compounds were screened for pharmacokinetic profile and drug likeness as an important consideration for the selection of compounds with desirable prosperities using ADMETlab tools. Ligand-receptor analysis revealed Lantadene parent nuclei and their modified analogues as potent inhibitors of nuclear factor-kappa B receptor based on binding energy (-21.16 to-42.56 kcal/mol), number of interactions and bond length. Furthermore, most of the analogues were found to have good ADMET profiles. Cumulative computational analyses provided the lead Lantadene analogue 10 and can be considered as a potential candidate for detailed mechanistic studies against lung cancer.

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Synthesis of lantadene analogs with marked in vitro inhibition of lung adenocarcinoma and TNF-α induced nuclear factor-kappa B (NF-κB) activation

Cited by 13 publications

References 18 publications

In vitro antitumor effects of two novel oligostilbenes, cis- and trans-suffruticosol D, isolated from Paeonia suffruticosa seeds

In vitro antitumor effects of two novel oligostilbenes, cis- and trans-suffruticosol D, isolated from Paeonia suffruticosa seeds

Network Pharmacology to Explore Active Components and Pharmacological Mechanism of Action of Compound Longmai Ning Decoction for the Treatment of Myocardial Infarction

Lantadenes Targeting NF-ΚB in Cancer: Molecular Docking and ADMET Predictions

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