Isoflavonoid Derivatives Research Articles

Synthesis, XRD/HSA-interactions, synthon, TD-DFT/optical analysis, docking and antibacterial evaluation of two (±)-Isoflavonoid derivatives

A high-yield synthesis of the new racemic (±)-2-(1-bromoethyl)-7‑methoxy-3-(4-methoxyphenyl)-4H-chromen-4-one was achieved in two steps by O- and 2-C-methylation 7,4′-dihydroxy-2-methylisoflavone, followed by radical bromination of the allylic methylene moiety using N-bromosuccinimide. XRD-crystallography, NMR, UV–vis CHN-EA, and FT-IR were all used to establish the identity and structure of the target ligand. Both the XRD, Hirshfeld surface area (HSA) and the DFT structural optimization validated the (±)‑bromo-chromen-4-one structural formula. XRD analysis reveals two types of synthons due to the presence of multiple short interactions, including CMe-H.....Br/Cph-H.....O and H…πCC. There is a high harmony between the experimental XRD-structural parameters and their DFT counterparts; additionally, the optical characteristics were derived by comparing the experimental UV–Vis result to the TD-DFT/B3LYP and TD-DFT/CAM-B3LYP ones. The compounds capacity to bind to DNA was assessed via the molecular docking technique with the use of 1BNA. The antibacterial activity of the produced (±)‑bromo-chroman-4-one and (±)-the non bromo‑chroman-4-one derivatives was evaluated against eight bacterial strains.

A new isoflavonoid derivative, evaluation of the antioxidant capacity and phenolic content of Genista lobelii DC

The phytochemical investigation of both chloroform and ethyl acetate extracts of Genista lobelii DC from an Algerian endemic plant led to the isolation of a new isoflavonoid Aspalathoidin compound (1) and nine known compounds (laburnetin, isokaempferide, retamasin B, ephedrodin, sakuretin, isoprunetin, genistein −7-O-β-glucoside, derrone-4′-O-methyl ether and eriodictyol-7,3′-dimethylether). Twelve phenolic compounds were identified in ethyl acetate and n-butanol extracts through a qualitative investigation of phenolic compounds using HPLC. Finally, both extracts were estimated for their phenolic and flavonoid contents as well as the evaluation of their antioxidant activity using five different assays DPPH, CUPRAC, ABTS, GOR and the sun protection factor SPF was determined as an index of the photoprotective capacity of the G.lobelii DC extracts. The extract of chloroform and ethyl acetate has good antioxidant and includes significant levels of phenolic and flavonoid components.

Bioprospecting microbes and enzymes for the production of pterocarpans and coumestans.

The isoflavonoid derivatives, pterocarpans and coumestans, are explored for multiple clinical applications as osteo-regenerative, neuroprotective and anti-cancer agents. The use of plant-based systems to produce isoflavonoid derivatives is limited due to cost, scalability, and sustainability constraints. Microbial cell factories overcome these limitations in which model organisms such as Saccharomyces cerevisiae offer an efficient platform to produce isoflavonoids. Bioprospecting microbes and enzymes can provide an array of tools to enhance the production of these molecules. Other microbes that naturally produce isoflavonoids present a novel alternative as production chassis and as a source of novel enzymes. Enzyme bioprospecting allows the complete identification of the pterocarpans and coumestans biosynthetic pathway, and the selection of the best enzymes based on activity and docking parameters. These enzymes consolidate an improved biosynthetic pathway for microbial-based production systems. In this review, we report the state-of-the-art for the production of key pterocarpans and coumestans, describing the enzymes already identified and the current gaps. We report available databases and tools for microbial bioprospecting to select the best production chassis. We propose the use of a holistic and multidisciplinary bioprospecting approach as the first step to identify the biosynthetic gaps, select the best microbial chassis, and increase productivity. We propose the use of microalgal species as microbial cell factories to produce pterocarpans and coumestans. The application of bioprospecting tools provides an exciting field to produce plant compounds such as isoflavonoid derivatives, efficiently and sustainably.

Inhibitory Effects of Thermolysis Transformation Products of Rotenone on Nitric Oxide Production.

Rotenone, isolated from Derris, Lonchocarpus, and Tephrosia from the family Fabaceae, has been shown to have a variety of biological properties and is used in various agricultural industries as a potent biopesticide. However, recent reports have demonstrated that rotenone has the potential to cause several adverse effects such as a neurodegenerative disease. This study aimed to induce thermolysis of the biopesticide rotenone and enhance the functionality of the degraded products. Rotenone (1) was degraded after autoclaving for 12 h, and the thermolytic reactants showed enhanced anti-inflammatory capacity against nitric oxide (NO) production. The structures of the newly modified products were spectroscopically determined. The thermal reaction products included various isoflavonoid derivatives 2-6, whose structures were characterized as being produced via chemical reactions in rotenone at the C-12 positions. Among the degraded products, (-)-tubaic acid (6) exhibited significantly improved anti-inflammatory effects compared to the original rotenone. Quantitative LC-MS analysis of the major thermolysis products generated in Derris extract containing rotenone was performed using isolate 2-5 purified from autoclaved rotenone. These results suggest that the thermal transformation of rotenone can improve the functionality of anti-inflammatory agents.

Rotenoids and Isoflavones from Xeroderris stuhlmannii (Taub.) Mendonça & E.P. Souza and Their Biological Activities.

The phytochemical study of the ethanolic extract of the leaf of Xeroderris stuhlmannii led to the isolation of five hitherto unreported compounds including two isoflavones (1-2), and three rotenoids (3-5), along with eight known isoflavonoid derivatives (6-13) and one pterocarpan derivative (14). The structures of the new compounds and those of the known ones were established by the spectroscopic (1D and 2D NMR) and spectrometric (HRESIMS) techniques as well as a comparison of their spectroscopic data with those reported in the literature. The leaf extract, fractions, and isolated compounds were tested for their antibacterial effects against nine bacterial strains. Compounds 3, 8, 11, and 12 showed a significant antibacterial effect, with a minimum inhibitory concentration (MIC) value of 62.5 µg/mL each, against Salmonella typhi, Staphylococcus aureus, Klessiella pneumonae, and Escherichia coli, respectively. In addition, the leaf extract, fractions, and isolated compounds were tested for their antifungal effects against four fungal strains. The hexane fraction showed a significant antifungal effect with an MIC value of 125 µg/mL against Candida parasilosis, whereas compounds 3, 8, and 12 showed significant antifungal activity with an MIC value of 62.5 µg/mL, each against Candida parasilosis, Candida albicans, and Candida krusei, respectively.

Anti-Inflammatory Activity of Cajanin, an Isoflavonoid Derivative Isolated from Canavalia lineata Pods.

The bioactive components of Canavalia lineata (Thunb.) DC pods were investigated using bioactivity-guided isolation, and the chemical structures of flavonoids 1–3, isoflavonoid derivatives 4–11, and phenolic compounds 12 and 13 were identified by comparing NMR, MS, and CD spectral data with previously reported spectroscopic data. Compounds 1–13 were evaluated for their anti-inflammatory effects on LPS-stimulated RAW264.7 macrophages. Among these compounds, the isoflavonoid derivative cajanin (7) exhibited the most potent anti-inflammatory activity (IC50 of NO = 19.38 ± 0.05 µM; IC50 of IL-6 = 7.78 ± 0.04 µM; IC50 of TNF-α = 26.82 ± 0.11 µM), exerting its anti-inflammatory effects by suppressing the activation and nuclear translocation of the transcription factor NF-κB by phosphorylating IκB and p65. These results suggested that cajanin (7) may be a potential candidate for improving the treatment of inflammatory diseases.

Qualitative and Quantitative Phytochemical Analysis of Ononis Hairy Root Cultures.

Hairy root cultures are genetically and biochemically stable, and they regularly possess the same or better biosynthetic capabilities for specialized (secondary) metabolite production compared to the intact plant. Ononis species are well-known herbal remedies in ethnopharmacology and rich sources of isoflavonoids. Besides isoflavones, less prevalent isoflavones and pterocarpans with valuable biological effects can be found in Ononis species as well. As these plants are only collected but not cultivated, biotechnological methods could play a role in the larger-scale extraction of Ononis isoflavonoids. Regarding this information, we aimed to establish Ononis spinosa and Ononis arvensis hairy root cultures (HRCs) and analyze the isoflavonoid profile of hairy root cultures qualitatively and quantitatively, in order to define their capacity to produce biologically valuable isoflavonoids. During the qualitative description, beside isoflavonoids, two new phenolic lactones, namely, bulatlactone 2″-O-β-D-glucoside and ononilactone, were isolated, and their structures were characterized for the first time. Altogether, 29 compounds were identified by the means of UPLC-Orbitrap-MS/MS. Based on UHPLC-UV-DAD measurements, the isoflavonoid spectrum of the Ononis HRCs differed markedly from wild-grown samples, as they produce a limited range of the scaffolds. The most abundant compounds in the HRCs were medicarpin glucoside and sativanone glucoside. The overall isoflavonoid production of the cultures was comparable to wild-grown O. arvensis and approximately twice as high as in wild-grown O. spinosa samples. As the overall content of wild-grown samples include more isoflavonoid derivatives, the HRCs contain structurally less divergent isoflavonoids but in higher quantity.

A Catalyst‐Free Synthetic Route to Modified Isoflavone via Multi‐Component Reaction

AbstractA concise and efficient one‐pot sequential approach for the synthesis of modified isoflavone was developed from a reaction of 3‐formylchromones, malononitrile, various α,α‐dicyanoolefines, using Et3N as the base, and EtOH as the solvent, in good yield. The value of this method lies in its short reaction time, convenient purification, no need for a metal catalyst, excellent efficiency, and green solvent. This synthesis involves a Knoevenagel condensation/carbanion formation/ring closure, and finally, an elimination to obtain the respective isoflavonoid derivatives.

Substituent Effects on the Radical Scavenging Activity of Isoflavonoid.

Understanding the role of substituents is of great importance for the preparation of novel phenolic compounds with enhanced antioxidative properties. In this work, the antioxidative activity of isoflavonoid derivatives with different substituents placed at the C2 position was determined by density functional theory (DFT) calculations. The bond dissociation enthalpy (BDE), ionization potential (IP), and proton affinity (PA) related to hydrogen atom transfer (HAT), single electron transfer-proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET) mechanisms were calculated. The strongest antioxidative group of isoflavonoid is not altered by the substituents. Excellent correlations were found between the BDE/IP/PA and Hammett sigma constants. Equations obtained from linear regression can be useful in the selection of suitable candidates for the synthesis of novel isoflavonoids derivatives with enhanced antioxidative properties. In the gas and benzene phases, the electron-donating substituents would enhance the antioxidative activity of isoflavonoids via weakening the BDE of 4′−OH. In water phase, they will reduce the antioxidative by strengthening the PA of 7−OH. Contrary results occur for the electron-withdrawing groups. In addition, the electronic effects of substituents on the BDE/IP/PA have also been analyzed.

Diadzein complexation with unmodified cyclodextrins: A detailed experimental and theoretical study

We investigated daidzein (DZ) as an isoflavonoid derivative complexed with the unmodified cyclodextrin (α-, β-, and γ-CDs) molecules as the enthalpy-driven and exothermic reactions. The analysis of experimental and computational data obtained mainly from spectroscopic methods (1H NMR and FT-IR), molecular docking, and all-atom molecular dynamics simulations (MM-GBSA and MM-PBSA) revealed the strongest and more stable complexation of DZ with the β-CD compound mediated by H-bonds and hydrophobic interactions. These results highlight the possibility to use this formulation as a food supplement with antioxidant activity and improved bioavailability, solubility, and stability, lowering the risk of some hormone-related cancers and heart disease.

Scandenolone, a natural isoflavone derivative from Cudrania tricuspidata fruit, targets EGFR to induce apoptosis and block autophagy flux in human melanoma cells

Natural isoflavones have been reported to have a potential of antineoplastic activity. However, novel and specific isoflavones are still needed to be explored, and the underlying molecular mechanisms and the intracellular targets of these compounds remain elusive. In our study, we discovered that scandenolone, a natural isoflavonoid derivative from Cudrania tricuspidata fruit, exhibited antineoplastic activity in SK-MEL-28 cells by inducing intrinsic apoptosis and blocking autophagy flux. In addition, scandenolone significantly induced G2/Mcycle arrest and inhibited cell migration. The study of the intracellular molecular targets showed that scandenolone binds directly to the active kinase and ATP-binding site of EGFR, which results in downregulating the AKT/mTOR/ERK signaling pathway. Therefore, out results indicate that scandenolone from Cudrania tricuspidata fruit, significantly sensitized SK-MEL-28 cells to apoptosis and repressed the proliferation of the cells, which showed an enormous potential to treat melanoma.

Trypanocidal Activity of 2,5-Diphenyloxazoles Isolated from the Roots of Oxytropis lanata.

Eleven 2,5-diphenyloxazole derivatives (1-11), together with six known isoflavonoid derivatives, were isolated from the roots of Oxytropis lanata. The 2,5-diphenyloxazole (1) obtained proved to be identical to a standard sample used as a scintillator and liquid laser dye. The other oxazole derivatives isolated were found to have one to four hydroxy and/or O-methyl groups in their phenyl rings. Seven of the oxazole derivatives obtained are new (3-9). The inhibitory activity of the isolated compounds was evaluated against Trypanosoma congolense, the causative agent of African trypanosomosis in animals. Oxazoles with di- and trihydroxy groups showed trypanocidal activity, and 2-(2',3'-dihydroxyphenyl)-5-(2″-hydroxyphenyl)oxazole (4) exhibited the most potent inhibitory activity (IC50 1.0 μM).

Rapid Characterization and Identification of Flavonoids in Radix Astragali by Ultra-High-Pressure Liquid Chromatography Coupled with Linear Ion Trap-Orbitrap Mass Spectrometry.

A simple and effective method was established for separation and characterization of flavonoid constituents in Radix Astragali (RA) by combination of ultra-high-pressure liquid chromatography with LTQ-Orbitrap tandem mass spectrometry (u-HPLC-LTQ-Orbitrap-MS(n)). For three major structural types of flavonoids, the proposed fragmentation pathways and major diagnostic fragment ions of isoflavones, pterocarpans and isoflavans were investigated to trace isoflavonoid derivatives in crude plant extracts. Based on the systematic identification strategy, 48 constituents were rapidly detected and characterized or tentatively identified, many of which were first reported in RA. The u-PHLC-LTQ-Orbitrap MS(n) platform was proved as an effective tool for rapid qualitative analysis of secondary metabolite productions from natural resources.

Development of a general approach to the synthesis of a library of isoflavonoid derivatives

Isoflavonoids are a class of organic compounds that act primarily as antioxidants. They are produced almost exclusively by various members of the bean family including soybeans, tofu, peanuts, chick peas, and alfalfa. The antioxidant characteristics that isoflavonoids exhibit help hinder the progression of certain cancers, primarily breast, prostate, and colon cancer. We have developed a three-five step synthesis for obtaining a suite of isoflavonoid derivatives. The synthesis involves an enamine formation, a ring closure and halogenation, a Suzuki coupling, and finally a global deprotection to obtain the respective isoflavonoid derivatives.

Theoretical and experimental studies of new modified isoflavonoids as potential inhibitors of topoisomerase I from Plasmodium falciparum.

DNA topoisomerase I from Plasmodium falciparum (PfTopoI), a potential selective target for chemotherapy and drug development against malaria, is used here, together with human Topo I (HssTopoI), for docking, molecular dynamics (MD) studies and experimental assays. Six synthetic isoflavonoid derivatives and the known PfTopoI inhibitors camptothecin and topotecan were evaluated in parallel. Theoretical results suggest that these compounds dock in the binding site of camptothecin and topotecan inside both enzymes and that LQB223 binds selectively in PfTopoI. In vitro tests against P. falciparum blood parasites corroborated the theoretical findings. The selectivity index (SI) of LQB223 ≥98 suggests that this molecule is the most promising in the group of compounds tested. In vivo experiments in mice infected with P. berghei showed that LQB223 has an antimalarial activity similar to that of chloroquine.

HPLC-Based Activity Profiling for GABAA Receptor Modulators in Adenocarpus cincinnatus

In a two-microelectrode voltage clamp assay with Xenopus laevis oocytes, a dichloromethane extract of Adenocarpus cincinnatus roots and tubers (Leguminosae) enhanced the GABA-induced chloride current (IGABA) through receptors of the subtype α1β2γ2s by 126.5 ± 25.1% when tested at 100 μg/mL. By means of HPLC-based activity profiling, 15 flavonoid and isoflavonoid derivatives, including eight new compounds, were identified in the active fractions of the extract. Isoflavone 11 and pterocarpans 2 and 8 showed promising activity in the oocyte assay, with EC50 values between 2.8 ± 1.4 and 18.8 ± 2.3 μM. Maximal potentiation of IGABA ranged between 490% and 640%. This is the first report of pterocarpans as GABAA receptor modulators.

Isoflavonoid derivatives from Adenocarpus cincinnatus as positive GABAA receptor modulators

GABAA receptors are the major inhibitory receptors in the CNS, and the target for benzodiazepines, barbiturates, and various other CNS depressants. Such drugs, however, lack selectivity for different GABAA receptor subtypes and thus, the pharmacological treatments of anxiety, epilepsy, insomnia, and mood disorders are accompanied by serious side effects. Consequently, the search for selective modulators with new scaffolds is still an urgent task.

Correlation between Antioxidative Activities and Metabolite Changes duringCheonggukjangFermentation

Liquid chromatography mass spectrometry and multivariate analysis were employed to investigate the correlation between fermentation time-dependent metabolite changes in cheonggukjang, a traditional fermented soybean product, and changes in its antioxidant activity over 72 h. The metabolite patterns were clearly distinguished not by strains but by fermentation time, into patterns I (0-12 h), II (12-24 h), and III (24-72 h), which appeared as distinct clusters on principal component analysis. The compounds that significantly contributed to patterns I, II, and III were soyasaponins, isoflavonoid derivatives, and isoflavonoid aglycons respectively. Partial least square analysis for metabolite to antioxidant effects showed correlations between the ferric reducing/antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay during 24-36 h, and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) test and total phenol content (TPC) during 36-72 h. Compared with the strong negative correlations of glucosylated-isoflavonoids with DPPH, ABTS and TPC during fermentation, the isoflavonoid aglycon displayed strong positive correlations with these compounds during fermentation.

Isoflavonoid Derivatives from Lophira alata Stem Heartwood

Six isoflavonoid derivatives among which three are new have been isolated from the stem heartwood of Lophira alata. The structures were elucidated from spectroscopic and chemical evidences. Two have unusual carbon skeletons, possibly resulting from a variant of isoflavonoid biogenesis. The two compounds form the first members of a new subclass of flavonoid compounds which we call "isobiflavonoids". The presence of these isoflavonoid compounds in this plant of the Ochnaceae family has important chemotaxonomic implications since it modifies the botanic distribution of isoflavonoid compounds in non-leguminous plants.

Isoflavonoid Derivatives from Lophira alata Stem Heartwood

Isoflavonoid Derivatives from Lophira alata Stem Heartwood