Chrysin Derivatives Research Articles

Synthesis and antiproliferative evaluation of novel chrysin selenocyanates

Selenocyano fragments with distinct structural characteristics were successfully incorporated into the 5- and 7-positions of chrysin via etherification and esterification of its hydroxyl groups. Eleven novel chrysin selenocyanates were synthesized, and their structures characterized by NMR and HRMS. The activities of all compounds were evaluated against human cervical cancer cell lines HeLa, ovarian cancer cell lines SKOV-3, and breast carcinoma cell lines MCF-7 using MTT assays. Results indicated that esterified chrysin derivatives significantly inhibited HeLa cells, while alkylated chrysin ethers showed notable activity against SKOV-3 and MCF-7 cells. Compounds 5c and 5e exhibited the strongest inhibitory effects on SKOV-3 cells, with IC50 values of 2.27 ± 0.19 μM and 2.51 ± 0.33 μM, respectively. The introduction of diselenocyanate at both the 5- and 7-positions demonstrated superior inhibitory activity compared to a single selenocyanate at the 7-position alone. The findings may aid in designing novel chemotherapeutic drugs.

In Vitro Inducted Tetraploid Elsholtzia splendens Nakai ex F. Maek. Alters Polyphenol Species and Synthesis.

Elsholtzia splendens Nakai ex F. Maek. has been employed in traditional Chinese medicine for millennia. Nevertheless, the small size and the paucity of research on its pharmacological effects have restricted its extensive utilisation in clinical medicine. Polyploid breeding represents an effective method for the rapid enhancement of plant biomass and metabolites. In this study, the most effective in vitro method for inducing tetraploid formation was identified as axillary buds treated in a solution of colchicine at a concentration of 1% for 24 h. Meanwhile, a comparison between tetraploids and diploids yielded two significant findings: (1) The presence of 6-zonocolpate and 8-zonocolpate pollen grains can be used as distinguishing characteristics for diploid and tetraploid, respectively. (2) Genome duplication resulted in alterations to the polyphenol species and synthesis pathway in E. splendens. The accumulation of wogonin, oroxylin A, baicalin, chrysin, acacetin and related derivatives was markedly greater in tetraploid plants, whereas apigenin, naringenin, scutellarein and related derivatives were found to accumulate to a greater extent in diploid plants. It is noteworthy that wogonin and oroxylin A were uniquely detected in tetraploids, indicating that the generated tetraploids may harbor novel pharmacological value. The findings not only provided new insights into the metabolic mechanism of polyploidisation but also established a foundation for the selection and breeding of novel genetic resources of E. splendens.

Synthesis and Bioevaluation of New Stable Derivatives of Chrysin-8-C-Glucoside That Modulate the Antioxidant Keap1/Nrf2/HO-1 Pathway in Human Macrophages

Background/Objectives: The beneficial effects of the flavonoid chrysin can be reduced by its poor oral bioavailability. It has been shown that chrysin-8-C-glucoside (1) has a better absorption capability. The aim of this study was to evaluate the antioxidant and anti-inflammatory activity of this glucoside, as well as the respective hexa-acetate derivative 1a and the hexa-ethyl carbonate derivative 1b since the inclusion of moieties in bioactive molecules may increase or modify their biological effects. Methods: THP-1 macrophages were used to determine the viability in the presence of chrysin derivatives, and non-cytotoxic concentrations were selected. Subsequently, lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) production and inflammatory mediators were examined. The involvement of chrysin derivatives with the Keap1 and Nrf2 antioxidant system was determined by docking and Western blotting studies. Results: Our data demonstrated, for the first time, that pretreatment with the three compounds caused a significant reduction in LPS-induced reactive oxygen species (ROS) production and pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) levels, as well as in cyclooxygenase 2 (COX-2) expression. The mechanisms underlying these protective effects were related, at least in part, to the competitive molecular interactions of these phenolic compounds with Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2), which would allow the dissociation of Nrf2 and its translocation into the nucleus and the subsequent up-regulation of hemo-oxygenase 1 (HO-1) expression. Conclusions: Compared to the 8-C-glucoside parent chrysin, compound 1a exhibited the strongest antioxidant and anti-inflammatory activity. We hypothesized that the incorporation of an acetate group (1a) may reduce its polarity and, thus, increase membrane permeability, leading to better pharmacological activity. These findings support the potential use of these phenolic compounds as Nrf2 activators against oxidative-stress-related inflammatory diseases.

Protective effect of evodiamine on acetic acid-induced gastric ulcers in rats through regulation of ROS/ICAM1/Nrf2 signaling pathway

Purpose: To investigate the anti-inflammatory and antiprotozoal effects as well as chemical profile of ethanol extracts of Hedyotis diffusa (Rubiaceae) (HDE) and Scutellaria barbata (Lamiaceae) (SBE). Methods: Dried whole plants collected in Vietnam were extracted with ethanol (30 and 96 %) by maceration for 4 weeks. The resulting extracts obtained after evaporating the solvent were stored in a refrigerator at 4 oC. Mouse carrageenan-induced inflammation and mouse macrophage cell line RAW264.7 were used to assess the in vivo and in vitro anti-inflammatory activities, respectively, while ciliate, Tetrahymena pyriformis was used to determine antiprotozoal effects. Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was employed to analyze the chemical profiles of the extracts. Results: All the extracts manifested anti-inflammatory effects in vitro and in vivo. The HDE exhibited significantly higher in vitro anti-inflammatory activity than SBE (p < 0.05). Furthermore, in vivo antiinflammatory activity was higher in SBE compared to HDE. Both extracts exhibited antiprotozoal effects. The 96 % ethanol extract of both plants were more active than the 30 % ethanol extracts. Analysis by UHPLC‐Q‐TOF- MS revealed the presence of chrysin, apigenin and apigenin derivatives, naringenin, wogonin, quercetin and quercetin derivatives, as well as scutellarin. Conclusion: The HDE and SBE extracts from Vietnam exhibit significant in vivo and in vitro antiinflammatory activities and in addition, antiprotozoal activity against Tetrahymena pyriformis. These plants, therefore, are potential sources of antiprotozoal agents.

Discovery of novel chrysin derivatives as potential Anti-Psoriasis agents

Psoriasis is a chronic inflammatory disease and is difficult to cure. In this work, a series of novel chrysin derivatives have been designed and prepared while evaluating anti-inflammatory activities in vitro and in vivo. In vitro, RAW264.7 cells were used to detect the inflammatory activities at first, and compounds 4h, 4k, and 4o significantly decreased the levels of NO, TNF-α, and IL-6. In particular, compound 4o showed superior anti-inflammatory activities than other compounds. Moreover, compound 4o decreased the level of IL-17A in LPS-induced HaCaT cells in vitro. The effect and mechanism of anti-inflammatory activities on psoriasis were determined by imiquimod (IMQ)-induced psoriasis-like mice in vivo. Compound 4o deduced the level of IL-6, IL-17A, IL-22, IL-23, and TNF-α, and showed potent anti-psoriasis activity. Further mechanism study suggested that compound 4o could improve the skin inflammation of psoriasis by inhibiting the NF-κB and STAT3 signaling pathways.

Synthesis and biological evaluation of chrysin derivatives containing α-lipoic acid for the treatment of inflammatory bowel disease.

This study introduces newly discovered chrysin derivatives that show potential as candidate molecules for treating inflammatory bowel disease (IBD). Compound 4b, among the synthesized compounds, displayed significant inhibitory effects on monocyte adhesion to colon epithelium induced by TNF-α, with an IC50 value of 4.71μM. Further mechanistic studies demonstrated that 4b inhibits the production of reactive oxygen species (ROS) and downregulates the expression of ICAM-1 and MCP-1, key molecules involved in monocyte-epithelial adhesion, as well as the transcriptional activity of NF-κB. In vivo experiments have shown that compound 4b exhibits a dose-dependent inhibition of 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats, thereby validating its effectiveness as a colitis inhibitor in animal models. These results indicate that 4b shows considerable promise as a therapeutic agent for managing IBD.

Design, synthesis, and biological evaluation of novel chrysin derivatives as poly(ADP-ribose) polymerase 1 (PARP1) inhibitors for the treatment of breast cancer

In this study, we reported the discovery and structure-activity relationship analysis of chrysin derivatives as a new class of inhibitors targeting poly (ADP-ribose) polymerase 1 (PARP1). Among these derivatives, compound 5d emerged as the most effective chrysin-based inhibitor of PARP1, with an IC50 value of 108 nmol·L−1. This compound significantly inhibited the proliferation and migration of breast cancer cell lines HCC-1937 and MDA-MB-436 by inducing DNA damage. Furthermore, 5d induced apoptosis and caused an extended G1/S-phase in these cell lines. Molecular docking studies revealed that 5d possesses a strong binding affinity toward PARP1. In vivo, in a xenograft model, 5d effectively reduced tumor growth by downregulating PARP1 expression. Overall, compound 5d shows promise as a potential therapeutic agent for the treatment of BRCA wild-type breast cancer.

CM1, a Chrysin Derivative, Protects from Endotoxin-Induced Lethal Shock by Regulating the Excessive Activation of Inflammatory Responses.

Sepsis, a leading cause of death worldwide, is a harmful inflammatory condition that is primarily caused by an endotoxin released by Gram-negative bacteria. Effective targeted therapeutic strategies for sepsis are lacking. In this study, using an in vitro and in vivo mouse model, we demonstrated that CM1, a derivative of the natural polyphenol chrysin, exerts an anti-inflammatory effect by inducing the expression of the ubiquitin-editing protein TNFAIP3 and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Interestingly, CM1 attenuated the Toll-like receptor 4 (TLR4)-induced production of inflammatory cytokines by inhibiting the extracellular-signal-regulated kinase (ERK)/MAPK and nuclear factor kappa B (NF-κB) signalling pathways. In addition, CM1 induced the expression of TNFAIP3 and SIRT1 on TLR4-stimulated primary macrophages; however, the anti-inflammatory effect of CM1 was abolished by the siRNA-mediated silencing of TNFAPI3 or by the genetic or pharmacologic inhibition of SIRT1. Importantly, intravenous administration of CM1 resulted in decreased susceptibility to endotoxin-induced sepsis, thereby attenuating the production of pro-inflammatory cytokines and neutrophil infiltration into the lung compared to control mice. Collectively, these findings demonstrate that CM1 has therapeutic potential for diverse inflammatory diseases, including sepsis.

In Silico Screening of Chrysin Derivatives as Drug Leads Against Covid-19

The current investigation was aimed at in silico studies of some selected chrysin derivatives to evaluate their activity in attenuation of COVID 19. In this study 50 chrysin derivatives were selected and Remedesivir was used as standard in assessing the anti-viral activity. To assess the ADMET potential of compounds, primarily drug-like properties and bioactivity scores were calculated. Using PATCHDOCK software, binding fitness scores for SARS COV2 protease and Angiotensin Converting Enzyme proteins were determined using molecular docking studies. According to results of in silico studies, derivatives of chrysin may offer promising leads for development of drugs with good antiviral properties against COVID 19.

Binding patterns of derivatives of fisetin and chrysin to the enzyme complex cyclin-dependent kinase 6/cyclin D

Binding patterns of derivatives of fisetin and chrysin to the enzyme complex cyclin-dependent kinase 6/cyclin D

Design, synthesis, molecular docking, molecular dynamic simulation, and MMGBSA analysis of 7-O-substituted 5-hydroxy flavone derivatives

A series of chrysin derivatives were designed, synthesized, and evaluated for their antibacterial activity against four different bacterial strains. We have synthesized new propyl-substituted and butyl-substituted chrysin-piperazine derivatives, which show marvellous inhibition against E. coli and S. aureus. The free hydroxyl group at the C-5 position of chrysin improved therapeutic efficacy in vivo and was a beneficial formulation for chemotherapy. All synthesized compounds were confirmed by various spectroscopic techniques such as IR, NMR, HPLC, and mass spectrometry. The compounds exhibited moderate to good inhibition, and their structure–activity relationship (SAR) has also been illustrated. Among the synthesised compounds, compounds 4 and 10 were the most active against S. pyogenes and E. coli, with 12.5 g/mL MICs; additionally, compound 12 exhibits significant activity on both the S. aureus and E. coli stains. Based on the promising activity profile and docking score of compound 12, it was selected for 100 ns MD simulation and post-dynamic binding free energy analysis within the active sites of S. aureus TyrRS (PDB ID: 1JIJ) and E. coli DNA GyrB (PDB ID: 6YD9) to investigate the stability of molecular contacts and to establish how the newly synthesized inhibitors fit together in the most stable conformations. Communicated by Ramaswamy H. Sarma

Design, Synthesis, and In vitro Anticancer Activity of Novel Chrysin Derivatives

Background: Cancer is a serious threaten to human life, and drug developers are pushing hard to discover potent anticancer agents. Pyrimidine and flavonoids are both attractive entities in medicinal chemistry; it is necessary to get new cancer drugs capitalizing on the two frameworks. Objective: This work includes the synthesis of series chrysin derivatives containing different substituted pyrimidines and an evaluation of their in vitro anticancer activity. Methods: Chrysin was merged with different substituted pyrimidines. Their antiproliferative activity was screened against five cancer cell lines (A549, HepG2, HCT116, MCF-7, and PC-3) using MTS method, and the marketed anticancer drug erlotinib was used as a reference. Results: Seventeen chrysin derivatives were synthesized. Compound 33E showed the best activity against A549, HepG2, MCF-7, and PC-3 cells, with IC50 values of 30.30 μM, 21.02 μM, 24.67 μM, 22.13 μM in A549, HepG2, MCF-7, PC-3 cells, respectively. Compound 33A showed the best activity against HCT116 cells, with an IC50 value of 4.83 μM in HCT116 cell lines. Conclusion: In the present study, a new set of chrysin derivatives containing anilinopyrimidine, piperazine- pyrimidine and piperidine-pyrimidine were prepared. Two compounds (33D, 33E) display higher toxicity than erlotinib toward the five cancerous cell lines (A549, HepG2, HCT116, MCF-7, and PC-3), and one compound (33A) exhibits better inhibitory activity than erlotinib to the HCT116 cells. These results underline the significance of the

Synthesis and In Vitro Anticancer Evaluation of Chrysin Containing Hybrids and Other Chrysin Derivatives

Chrysin, a well-known naturally occurring flavonoid having several biological effects including antiproliferative activity, was coupled with different pharmacophore structures. Coupling was carried out with spacers of different lengths and types. Structures selected for hybrid formation were amines, cyclic amino acid esters, and (hetero)aromatic compounds. In addition, vindoline, which is a Vinca alkaloid containing an indole skeleton, was also used. The alkylation of amines in the presence of carbonate base resulted in an interesting carbamate side product formation beside the expected amine. We also present the detailed structure elucidation of the carbamates. The in vitro anticancer activities of the synthesized derivatives were examined against 60 human tumor cell lines in National Cancer Institute (NCI, USA).

Prenylated Chrysin Derivatives as Partial PPARγ Agonists with Adiponectin Secretion-Inducing Activity.

Decreased circulating adiponectin levels are associated with an increased risk of human metabolic diseases. The chemical-mediated upregulation of adiponectin biosynthesis has been proposed as a novel therapeutic approach to managing hypoadiponectinemia-associated diseases. In preliminary screening, the natural flavonoid chrysin (1) exhibited adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Here, we provide the 7-prenylated chrysin derivatives, chrysin 5-benzyl-7-prenylether compound 10 and chrysin 5,7-diprenylether compound 11, with the improved pharmacological profile compared with chrysin (1). Nuclear receptor binding and ligand-induced coactivator recruitment assays revealed that compounds 10 and 11 functioned as peroxisome proliferator-activated receptor (PPAR)γ partial agonists. These findings were supported by molecular docking simulation, followed by experimental validation. Notably, compound 11 showed PPARγ binding affinity as potent as that of the PPARγ agonists pioglitazone and telmisartan. This study presents a novel PPARγ partial agonist pharmacophore and suggests that prenylated chrysin derivatives have therapeutic potential in various human diseases associated with hypoadiponectinemia.

3D quantitative structure–activity relationships study on anti-gastric cancer of chrysin derivatives

3D quantitative structure–activity relationships study on anti-gastric cancer of chrysin derivatives

Untargeted Metabolomics Analysis of the Orchid Species Oncidium sotoanum Reveals the Presence of Rare Bioactive C-Diglycosylated Chrysin Derivatives.

Plants are valuable sources of secondary metabolites with pharmaceutical properties, but only a small proportion of plant life has been actively exploited for medicinal purposes to date. Underexplored plant species are therefore likely to contain novel bioactive compounds. In this study, we investigated the content of secondary metabolites in the flowers, leaves and pseudobulbs of the orchid Oncidium sotoanum using an untargeted metabolomics approach. We observed the strong accumulation of C-diglycosylated chrysin derivatives, which are rarely found in nature. Further characterization revealed evidence of antioxidant activity (FRAP and DPPH assays) and potential activity against neurodegenerative disorders (MAO-B inhibition assay) depending on the specific molecular structure of the metabolites. Natural product bioprospecting in underexplored plant species based on untargeted metabolomics can therefore help to identify novel chemical structures with diverse pharmaceutical properties.

Synthesis, single crystal characterization and anti-AD activities of a novel complex of Cu(II) with in situ formed protonated chrysin derivative ligand

Alzheimer's disease (AD), the most common form of neurodegeneration disorder in adults, is becoming the overwhelming burden on the healthcare and economic system. In this study, chrysin derivative with the morpholine moiety was designed, synthesized and evaluated based on the multi targets directed ligands strategy for the treatment of AD centered with therapeutic attempts to restore metal homeostasis. It selectively coordinated with the important bio-metal ions related AD, especially Cu2+. Notably, single crystals of both 1 and 1-Cu(II) were obtained and the single crystal structures were characterized by X-ray crystal diffraction, which provided a basis to further explore the possible structure-activity relationship at the molecular level. Compound 1 and 1-Cu(II) complex showed potent anti-oxidative activities, with respect to both ·OH and ·O2− scavenging properties In addition, 1 had good inhibitory activity on Aβ1–42 aggregation, and it could target copper dyshomeostasis through extracting Cu2+ from the amyloids. The studies in silico showed that 1 had brain availability and peroral bioavailability. Taken together, compound 1, as the derivative of chrysin, might be a promising advanced lead candidate for the development of new anti-AD drugs and it may provide a useful template for studying the structure-activity relationships of biometal-coordinating drugs.

Chrysin: A polyedric flavone as a tool to explore new phytotherapeutic applications and drug design.

In the field of pharmaceutical research, a branch that has become more and more interesting is phytochemistry. Among phytochemicals, flavonoids have been studied a lot over the past 30 years. This review summarizes the chemical characteristics, metabolism, applications, and toxicity of a particular flavonoid, chrysin, recorded in the last 10 years and supported by solid biological assays. Furthermore, this review highlights some derivatives of chrysin investigated to obtain more bioavailable molecules that maintain or improve chrysin's bioactivities, enclosing a chrysin patent section, as well.

Design, Synthesis, Characterization, Anti-Microbial, Anti-Oxidant, DNA, HSA, Cytotoxicity and Anti-Inflammatory Studies of Nitrogen-Substituted Chrysin Derivatives and Metal(II) Complexes

Design, Synthesis, Characterization, Anti-Microbial, Anti-Oxidant, DNA, HSA, Cytotoxicity and Anti-Inflammatory Studies of Nitrogen-Substituted Chrysin Derivatives and Metal(II) Complexes

A new series of chrysin derivatives as potent non-saccharide ⍺-glucosidase inhibitors

Twenty-three chrysin derivatives were designed and synthesized by alkylation and bromination reactions. Their structures were confirmed by NMR and mass spectrometry, and their in vitro ⍺-glucosidase (AG) inhibitory activity was investigated. Chrysin derivatives except for 3a, 3b, 2q, and 2r, revealed better activity than the reference acarbose with moderate to very strong inhibition against AG. Notably, 2f, 2j, and 4 showed very strong and strong effects on AG ⍺-glucosidase inhibitory activity with IC50 values of 0.08, 3.47, and 2.97 μM, respectively. Simultaneously, enzyme kinetics study indicated that 2f was a competitive-type inhibitor, while 2j and 4 were mixed-type inhibitors.