Bladder cancer (BC) is the 10th most common tumour with a high incidence and recurrence rate worldwide; however, the current therapies present limitations as, regularly, not all patients benefit from treatment. Therefore, the search for new, active marine phenolic acids with anti-tumour properties is imperative. In this study, we subjected marine phenolic acids to in silico investigations such as network pharmacology, molecular docking, and molecular dynamics simulation (MD) to identify a plausible pathway and the lead compound that inhibits BC. According to the network pharmacology analysis, eight hub genes (PLAU, MMP2, ITGB3, MAPK1, PTPN11, ESR1, TLR4, MMP9) were found and linked to the enrichment of hsa05205: proteoglycans in cancer, and four hub genes (MMP1, MMP2, MAPK1, MMP9) were involved in the enrichment of hsa05219: BC. Subsequently, molecular docking studies showed that the marine phenolic acids exhibit a strong binding affinity for the target protein, matrix metalloproteinase-9 (MPP9). Among these 14 marine phenolic acids, chicoric acid showed the highest binding affinity of -67.1445 kcal/mol and formed hydrogen bonds with the residues of Ala189, Gln227, Leu188, His226, Ala242, Arg249, Ala191, and Gly186 in the active site of the MPP9 protein. Then, molecular dynamics simulation revealed that chicoric acid formed a stable protein-ligand complex with RMSD and RMSF values of 0.72 nm and 0.53 nm, respectively. Furthermore, the PCA method was employed to understand the dynamical behaviour in the conformational space of MPP9 protein bound to chicoric acid, and the results showed the good conformational space behaviour of MPP9 protein. Moreover, chicoric acid showed a free binding energy value of -32.62 kcal/mol, which indicated it could be a BC inhibitor. Overall, chicoric acid demonstrated potential anti-BC activity through MPP9 protein inhibition.
Clinacanthus nutans has attracted Malaysian public interest due to its high medicinal value in the prevention of cancer. Currently, the specific compound or compounds giving rise to the anticancer potential of C. nutans has not been investigated thoroughly. The extraction was carried out by MeOH at room temperature using the powdered bark of C. nutans, while chromatography was carried out on a silica gel RP-18 column using the crude methanolic extract. Six fractions collected from column chromatography were evaluated by MTT assay against two breast cancer cell lines: MDA-MB-231 and MCF-7. Amongst the fractions, A12 and A17 were shown to exhibit the highest activity. Two sulphur-containing compounds, viz., entadamide C (1) and clinamide D (2), were isolated from these fractions. Molecular docking simulation studies revealed that entadamide C and clinamide D could bind favourably to the caspase-3 binding site with the binding energy of -4.28 kcal/mol and -4.84 kcal/mol, respectively. This study provides empirical evidence for the presence of sulphur-containing compounds in the leaves of C. nutans that displayed anticancer effects which explains its ethnomedicinal application against breast cancer. The docking simulation study showed that both compounds could serve as important templates for future drug design and development.
Targeting lipopolysaccharide (LPS)/toll-like receptor 4 signaling in mononuclear phagocytes has been explored for the treatment of inflammation and inflammation-related disorders. However, only a few key targets have been translated into clinical applications. Flavonoids, a class of ubiquitous plant secondary metabolites, possess a privileged scaffold which serves as a valuable template for designing pharmacologically active compounds directed against diseases with inflammatory components. This perspective provides a general overview of the diversity of flavonoids and their multifaceted mechanisms that interfere with LPS-induced signaling in monocytes and macrophages. Focus is placed on flavonoids targeting MD-2, IκB kinases, c-Jun N-terminal kinases, extracellular signal-regulated kinase, p38 MAPK and PI3K/Akt or modulating LPS-related gene expression.
Aim: The biggest cause of cancer deaths globally was lung cancer. New cancer fighting drugs are needed due to the rising number of cancer patients and cancer cells' treatment resistance.Results: Two Cu(II) complexes, synthesized from ligands based on 2-aminomethyl benzimidazole and salicylaldehyde derivatives, were designed and evaluated for their effectiveness against A549 lung cancer. The compounds were subjected to computational calculation using Density Functional Theory (DFT) to gather information on their reactivity. Furthermore, molecular docking are utilized to simulate the interaction between the compound and the MPP-9 protein. The synthesis of the ligands and their Cu(II) metal complexes are efficient and straightforward. The complexation between copper atom and the ligand are in 1:1 ratio. The MTT assay of the compounds against A549 lung carcinoma reveals that the both Cu(II) complexes good cytotoxicity activity, in comparison to their respective ligands. The low HOMO-LUMO band gap based on the DFT calculation predicts the high reactivity of the compounds. Furthermore, the low binding energy and the numbers of interactions of the Cu(II) complexes with MMP-9 protein binding site coincide with the antiproliferative activity tested in vitro.Conclusion: The cytotoxicity studies performed for Cu(L1Br) are promising, indicating a good candidate for a future drug.
The anti-inflammatory and immunosuppressive activities of plant secondary metabolites are due to their diverse mechanisms of action against multifarious molecular targets such as modulation of the complex immune system associated with rheumatoid arthritis (RA). This review discussed and critically analyzed the potent anti-inflammatory and immunosuppressive effects of several phytochemicals and their underlying mechanisms in association with RA in experimental studies, including preliminary clinical studies of some of them. A wide range of phytochemicals including phenols, flavonoids, chalcones, xanthones, terpenoids, alkaloids, and glycosides have shown significant immunosuppressive and anti-inflammatory activities in experimental RA models and a few have undergone clinical trials for their efficacy and safety in reducing RA symptoms and improve patient outcomes. These phytochemicals have potential as safer alternatives to the existing drugs in the management of RA, which possess a wide range of serious side effects. Sufficient preclinical studies on safety and efficacy of these phytochemicals must be performed prior to proper clinical studies. Further studies are needed to address the barriers that have so far limited their human use before the therapeutic potential of these plant-based chemicals as anti-arthritic agents in the treatment of RA is fully realized.
Aim: Chromones are promising for anticancer drug development.Methods & results: 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound 8 showed the highest cytotoxicity (LC50 3.2 μM) against colorectal cancer cells, surpassing 5-fluorouracil (LC50 4.2 μM). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound 8 directly binds to ULK1.Conclusion: Compound 8 is a promising lead for autophagy-modulating anti-colon cancer drugs.