Prioritization before dereplication, an effective strategy to target new metabolites in whole extracts: ghosalin from Murraya paniculata root.

Re-discovery of known metabolites is a common challenge in natural product-based drug discovery, and to avoid re-discovery, dereplication has been proposed for identifying known metabolites at the early stage of isolation. A majority of methods use LCMS to profile the extract and ignore the known mass. LC-HRMS profiling may generate a long mass list of metabolites. The identification of a new metabolite is difficult within the mass list. To overcome this, it was hypothesized that identifying a 'new metabolite' in the whole metabolome is more difficult than identifying it within the class of metabolites. A prioritization strategy was proposed to focus on the elimination of unknown and uncommon metabolites first using the designed bias filters and to prioritize the known secondary metabolites. The study employed Murraya paniculata root for the identification of new metabolites. The LC-HRMS-generated mass list of 509 metabolites was subjected to various filters, which resulted in 93 metabolites. Subsequently, it was subjected to regular dereplication, resulting in 10 coumarins, among which 3 were identified as new. Further, chromatographic efforts led to the isolation of a new coumarin, named ghosalin (1). The structure of the new compound was established through 2D NMR and X-ray crystallography. Cytotoxicity studies revealed that ghosalin has significant cytotoxicity against cancer cell lines. The proposed prioritization strategy demonstrates an alternative way for the rapid annotation of a particular set of metabolites to isolate a new metabolite from the whole metabolome of a plant extract.

Exploring the cytotoxic potential of biflavones of Araucaria cunninghamii: Precise identification combined by LC-HRMS-metabolomics and database mining, targeted isolation, network pharmacology, in vitro cytotoxicity, and docking studies.

The leaves of Araucaria cunninghamii are known to be nonedible and toxic. Previous studies have identified biflavones in various Araucaria species. This study aimed to investigate the in vitro cytotoxicity of the isolated compounds from Araucaria cunninghamii after metabolomics and network pharmacological analysis. Methanol extract of Araucaria cunninghamii leaves was subjected to bioassay-guided fractionation. The active fraction was analyzed using LC-HRMS, through strategic database mining, by comparing the data to the Dictionary of Natural Products to identify 12 biflavones, along with abietic acid, beta-sitosterol, and phthalate. Eight compounds were screened for network pharmacology study, where in silico ADME analysis, prediction of gene targets, compound-gene-pathway network and hierarchical network analysis, protein-protein interaction, KEGG pathway, and Gene Ontology analyses were done, that showed PI3KR1, EGFR, GSK3B, and ABCB1 as the common targets for all the compounds that may act in the gastric cancer pathway. Simultaneously, four biflavones were isolated via chromatography and identified through NMR as dimeric apigenin with varying methoxy substitutions. Cytotoxicity study against the AGS cell line for gastric cancer showed that AC1 biflavone (IC50 90.58 µM) exhibits the highest cytotoxicity and monomeric apigenin (IC50 174.5 µM) the lowest. Besides, the biflavones were docked to the previously identified targets to analyze their binding affinities, and all the ligands were found to bind with energy ≤-7 Kcal/mol.

New ring-A modified cycloartane triterpenoids from Dysoxylum malabaricum bark: Isolation, structure elucidation and their cytotoxicity.

The Genus Dysoxylum (Meliaceae) consists of approximately 80 species that are abundant in structurally diverse triterpenoids. The present study focused on isolating new triterpenoids from the bark of Dysoxylum malabaricum, one of the predominant species of Dysoxylum present in India. The methanol-dichloromethane bark extract was subjected to LCMS profiling followed by silica gel column chromatography and HPLC analysis to target new compounds. Two new ring A-modified cycloartane-type triterpenoids (1 and 2) were isolated from the bark extract. Spectroscopic methods like NMR, HRESIMS data, and electronic circular dichroism calculations elucidated the structuresandabsolute configurations of the isolated compounds. These compounds were evaluated for their cytotoxic potential against breast cancer cells and displayed notable cytotoxicity. Compound 1 exhibited the highest cytotoxicity against the MDA-MB-231 cells and induced apoptotic cell death. Also, it was able to inhibit glucose uptake and increase nitric oxide production in breast cancer cells.

Unveiling the healing properties of 2,3-dehydrosilychristin: a potential silymarin-derived flavonolignan from Vitex negundo.

The compound 2,3-dehydrosilychristin, a flavonolignan linked to silychristin and silymarin, remains intriguing due to its challenging isolation from silymarin. While silymarin has been the exclusive source of flavonolignans - silybin, silychristin and silydianin - 2,3-dehydrosilychristin is reported in this study from Vitex negundo Linn. leaves. 2,3-Dehydrosilychristin (7) and 14 other compounds were isolated through focused extraction. Its subsequent pharmacological evaluation demonstrated potent antioxidant and in-vitro anti-inflammatory effects, notably inhibiting cytokines TNF-α, IL-6, IL-8 and VEGF. In in-vivo assessments, 2,3-dehydrosilychristin (7) revealed remarkable hepatoprotective potential by reducing liver enzyme levels AST and ALT. These findings expand the potential of 2,3-dehydrosilychristin and suggest bioprospecting Vitex species as alternate sources of bioactive flavonolignans.

Isolation, Cytotoxicity, and In-silico Screening of Coumarins from Psoralea corylifolia Linn.

Psoralea corylifolia (syn. Cullen corylifolium), commonly called bawachi, is a medicinal plant extensively used for skin conditions like leukoderma, vitiligo, and psoriasis. It is notably rich in valuable bioactive compounds, particularly coumarins and furanocoumarins. This study isolated fourteen coumarins from P. corylifolia which were tested for cytotoxicity using the MTT assay, with compound 10 showing good cytotoxicity against A549 cells (IC50 0.9 µM), while compound 1, compound 2, and compound 3 displaying potential cytotoxicity against MDA-MB-231 cells (IC50 0.49 µM, 0.56 µM, and 0.84 µM respectively). Additionally, the compounds' interaction with Epidermal Growth Factor Receptor (EGFR) protein, highly expressed in both cell lines, was investigated through molecular modeling studies, that aligned well with cytotoxicity results. The findings revealed the remarkable cytotoxic potential of four coumarins 1, 2, 3, and 10 against A549 and MDA-MB-231 cell lines.