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The major environmental factor responsible for skin cancer is ultraviolet (UV) radiation, present in sunlight. UV radiation is directly linked to the production of reactive oxygen species (ROS), which accumulate in exposed cells and cause serious damage. The antioxidant systems present in cells cannot always sufficiently neutralize the ROS. Therefore, supplementation with exogenous antioxidants has been proposed. The antioxidant properties of some isoflavones, such as genistein, have already been well-proven. Genistein has limited bioavailability. However, its derivatives, with increased lipophilicity, could facilitate its transfer into cells, where they can expose its antioxidative potential. This study aims to investigate three genistein derivatives, with greater lipophilicity than the native compound, regarding their cytotoxicity, antioxidative properties, and effect on the cell cycle in normal human dermal fibroblasts (NHDF) and a melanoma cancer cell line (Me45). Results showed that lipophilic modification of the genistein molecule changes the biological response of NHDF and Me45 cell lines to UV-C radiation, but the lipophilicity cannot be directly linked with the activity of the compounds. A comparison of the effects of the genistein derivatives on healthy and cancerous cells suggests that their mode of action strongly depends on the type of cell involved. [ABSTRACT FROM AUTHOR]

The major environmental factor responsible for skin cancer is ultraviolet (UV) radiation, present in sunlight. UV radiation is directly linked to the production of reactive oxygen species (ROS), which accumulate in exposed cells and cause serious damage. The antioxidant systems present in cells cannot always sufficiently neutralize the ROS. Therefore, supplementation with exogenous antioxidants has been proposed. The antioxidant properties of some isoflavones, such as genistein, have already been well-proven. Genistein has limited bioavailability. However, its derivatives, with increased lipophilicity, could facilitate its transfer into cells, where they can expose its antioxidative potential. This study aims to investigate three genistein derivatives, with greater lipophilicity than the native compound, regarding their cytotoxicity, antioxidative properties, and effect on the cell cycle in normal human dermal fibroblasts (NHDF) and a melanoma cancer cell line (Me45). Results showed that lipophilic modification of the genistein molecule changes the biological response of NHDF and Me45 cell lines to UV-C radiation, but the lipophilicity cannot be directly linked with the activity of the compounds. A comparison of the effects of the genistein derivatives on healthy and cancerous cells suggests that their mode of action strongly depends on the type of cell involved.

Genistein is a phytoestrogen compound which possesses multiple biological activities such as anti-cancer, while its application is limited by poor pharmacokinetic properties. Structural modification is an effective approach to get genistein derivatives with better activities and approved pharmacokinetic properties. Based on previous research work, we synthesized two series of genistein derivatives bearing halogen substituents, and evaluated their inhibitory effects on the cancer cell lines MCF-7, MDA-MB-231, and MDA-MB-435. Among these derivatives, compound XI displayed the best inhibitory activity against MCF-7, MDA-MB-231 and MDA-MB-435 cell lines in vitro, which is worth further studies. [ABSTRACT FROM AUTHOR]

As a beneficial natural flavonoid, genistein has demonstrated a wide range of biological functions via regulating a number of targets and signaling pathways, such as anti-cancer, antioxidant, antibacterial, antiinflammatory, antifungal, antiviral, iron chelation, anti-obesity, anti-diabetes, and anti-hypertension. Pub- Med/Medline and Web of Science were searched using appropriate keywords until the end of December 2023. Despite its many potential benefits, genistein's clinical application is limited by low hydrophilicity, poor solubility, and suboptimal bioavailability due to its structure. These challenges can be addressed through the conversion of genistein into glycosides. Glycosylation of active small molecules may enhance their solubility, stability, and biological activity. In recent years, extensive research has been conducted on the synthesis, properties, and anticancer activity of glycoconjugates. Previous reviews were devoted to discussing the biological activities of genistin, with a little summary of the biosynthesis and the structure-activity relationship for their anticancer activity of genistein glycoside derivatives. Therefore, we summarized recent advances in the biosynthesis of genistein glycosylation and discussed the antitumor activities of genistein glycoside derivatives in a structure-activity relationship, which may provide important information for further development of genistein derivatives., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In this study two genistein derivatives (G1 and G2) are reported as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and differences in the inhibition of AChE are described. Although they differ in structure by a single methyl group, the inhibitory effect of G1 (IC50=264 nmol/L) on AChE was 80 times stronger than that of G2 (IC50=21,210 nmol/L). Enzyme-kinetic analysis, molecular docking and molecular dynamics (MD) simulations were conducted to better understand the molecular basis for this difference. The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE. The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area (MM/GBSA) method were consistent with the experimental data. The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions (ΔEele+ΔGGB) was responsible for the binding affinities of these two inhibitors. Additionally, analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124, Glu292, Val294 and Phe338 of AChE. In conclusion, the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds.

In this paper, the interaction of genistein (GEN) and its four derivatives (GEN1-4) with bovine serum albumin (BSA) were investigated by ultraviolet-visible absorption spectra, fluorescence, synchronous fluorescence, three-dimensional fluorescence spectroscopy, circular dichroism and molecular docking techniques. The experimental results showed that the intrinsic fluorescence of BSA was quenched by genisteins and was due to the formation of a genisteins-BSA complex. The quenching constant, binding constants, binding sites, intermolecular distances and thermodynamic properties were calculated at 298 K, 306 K and 310 K. Site marker competitive experiments indicated that the binding site of genisteins to BSA was mainly located in subdomain IIA. The conformational investigation showed that the presence of 0020 genisteins led to changes in the secondary structure of BSA and induced the slight unfolding of protein polypeptides, which confirmed some micro-environmental and conformational changes of BSA molecules. Furthermore, the binding affinity decreased in the order GEN1 > GEN > GEN4 > GEN3 > GEN2, which revealed that different type and position of substituents of genistein significantly influenced the affinity of compounds to BSA. The number of hydroxyl groups on the ring A was the most important factor because increasing the hydroxyl groups on ring A clearly enhanced the binding affinity. However, trifluoromethylation did not much affect the affinity, alkylation, esterification and difluoromethylation slightly enhanced the binding affinity. The results obtained herein will provide valuable information about the pharmacokinetics at a molecular level and be a useful guideline for the further design of much more suitable genistein derivatives. [ABSTRACT FROM AUTHOR]

Soy isoflavones exhibit various biological activities, such as antioxidant, anti-tumor, anti-inflammatory, and cardiovascular protective effects. The present study was designed to investigate the effects of sixteen synthesized 3-amino-2-hydroxypropoxy genistein derivatives on cell proliferation and activation of Nrf2 (Nuclear factor erythroid 2-related factor 2)/ARE (antioxidant response elements) pathway in human cancer cell lines. Most of the tested compounds exerted greater cytotoxic activity than genistein, as measured by MTT assay. Moreover, compound 8c showed the highest ARE-luciferase reporter activity among the test compounds. It strongly promoted Nrf2 nuclear translocation and up-regulated the expression of total Nrf2 and downstream targets NQO-1 and HO-1 at protein level. The present study may provide a basis for the application of isoflavone derivatives as Nrf2/ARE pathway inducers for cancer therapy and cancer prevention. [ABSTRACT FROM AUTHOR]

In this study two genistein derivatives (G1 and G2) are reported as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and differences in the inhibition of AChE are described. Although they differ in structure by a single methyl group, the inhibitory effect of G1 (IC 50 =264 nmol/L) on AChE was 80 times stronger than that of G2 (IC 50 =21,210 nmol/L). Enzyme-kinetic analysis, molecular docking and molecular dynamics (MD) simulations were conducted to better understand the molecular basis for this difference. The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE. The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area (MM/GBSA) method were consistent with the experimental data. The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions (Δ E ele +Δ G GB ) was responsible for the binding affinities of these two inhibitors. Additionally, analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124, Glu292, Val294 and Phe338 of AChE. In conclusion, the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds. [ABSTRACT FROM AUTHOR]

Genistein, due to its recognized chemopreventive and antitumour potential, is a molecule of interest as a lead compound in drug design. Recently, we found that the novel genistein derivative, [7- O-(2,3,4,6-tetra- O-acetyl-β-D-galactopyranosyl)-(1 → 4)-(6- O-acetyl-hex-2-ene-α-D-erythro pyranosyl)genistein, named G21, induced aberrations in mitotic spindle formation. In the presented study, we investigated the properties of G21 relevant to its genotoxic activity. The inhibition of topoisomerase IIα activity was evaluated in decatenation assay and immunoband depletion assay, the covalent DNA-topoisomerase IIα complexes and histone ɣH2AX were detected immunofluorescently. Genotoxic effects of the tested compounds were assessed in micronucleation assay. The presence of centromeres in the micronuclei and the multiplication of centrosomes were evaluated in fluorescence immunolabelled specimens. The inhibition of tubulin polymerization was measured spectrophotometrically. We found that both tested drugs were able to inhibit topoisomerase II activity; however, G21, in contrast to genistein, blocked this enzyme at the concentration far exceeding cytotoxic IC. We also found that both compounds caused micronucleation in DU 145 prostate cancer cells, but in contrast to genistein, G21 exhibited aneugenic activity, manifested by the presence of centromeres in micronuclei formed in cells treated with the drug. Aneugenic properties of G21 resulted from the inhibition of tubulin polymerization and centrosome disruption, not observed in the presence of genistein. The study supports and extends our previous observations that the mechanisms of cytotoxicity of genistein and its new glycosidic derivative-G21 are significantly different. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of the present paper was to assess the ability of genistein benzyl derivatives to interact with lipid bilayers. Calorimetric and fluorescence spectroscopic measurements revealed that, depending on the details of chemical structure, the studied compounds penetrated bilayers and affected their polar as well as hydrophobic regions. It was also found that physical state of bilayer played some role in flavonoid–lipid interactions. [Copyright &y& Elsevier]

Abstract: The ability of newly synthesized genistein benzyl and glycosylated derivatives to permeabilize the liposome membrane was studied by calcein-leakage method. All studied derivatives appeared to be more effective than their parent compound — genistein. Comparing the experimental results with theoretical calculations we found that in the case of benzyl derivatives the dipole moment of added benzene ring (with its substitutions) might be important for the strength of flavonoids–lipid interactions. This conclusion may have some implications for QSAR studies in which mostly the dipole moments of entire molecules are considered. [Copyright &y& Elsevier]

Abstract: A series of genistein derivatives, prepared by alkylation and difluoromethylation, were tested for their inhibitory effects on the hydrogen peroxide induced impairment in human umbilical vein endothelial (HUVE-12) cells in vitro. The HUVE-12 cells were pretreated with either the vehicle solvent (DMSO), genistein, or different amounts of the genistein derivatives for 30min before exposed to 1mM hydrogen peroxide for 24h. Cell apoptosis was determined by flow cytometry with propidium iodide (PI) staining. Cellular injury was estimated by measuring the lactate dehydrogenase (LDH) release. Data suggested that the genistein derivatives possessed a protective effect on HUVE-12 cells from hydrogen peroxide induced apoptosis and reduced LDH release. Among these derivatives, 7-difluoromethyl-5,4′-dimethoxygenistein exhibited the strongest activity against hydrogen peroxide induced apoptosis of HUVE-12 cells. [Copyright &y& Elsevier]

Abstract: Differential functionalization of the phenolic groups in genistein was carried out in excellent yields under ultrasonic irradiation. The isoflavone ring had proved to be unstable under stirring at 60°C and phenyl benzyl ketone was unexpectedly isolated instead of the genistein derivative. [Copyright &y& Elsevier]

Abstract: Genistein derivatives were synthesized from genistein through a facile sonochemical approach in high yields. The bioassay was performed on ovariectomized (OVX) rats in terms of bone mineral density (BMD) and the weight of bone ash (WBA) to lead to the discovery of eight novel genistein-based selective estrogen receptor modulators. Attention to the structure–activity relationship disclosed that the newly introduced 2-hydroxyethylthio scaffolds were essential for the anti-osteoporotic activity. Moreover, the anti-osteoporotic action of genistein, deprivable by methylation, could be restored and enhanced by subsequent sulfonation. The most promising compound was 4′,5,7-tri[3-(2-hydroxyethylthio)propoxy]isoflavone, displaying 24% (or 8%) increment in BMD and 31% (or 11%) increase in WBA of the femora relative to those discerned with the OVX (or genistein) group. Acute toxicity test showed that none of the active compounds was acutely toxic. [Copyright &y& Elsevier]

• Genistein derivatives with a carbonyl linker show higher bioavailability than the natural isoflavone. • Changing the structure of genistein can modulate its biological activity and bioavailability. • The presence of a sugar moiety in the genistein structure can reduce the speed of metabolism. The present study assesses the in vitro and in vivo bioavailability of genistein derivatives, hydroxyalkyl- and glycosyl alkyl ethers (glycoconjugates). Studies were carried out using compounds that exhibit higher in vitro antiproliferative activity in comparison with the parent isoflavone. Based on in vitro experiments using the Parallel Artificial Membrane Permeability Assay (PAMPA) and the Caco-2 cell monolayer permeability model, we found that modification of the isoflavone structure by O -alkylation improved bioavailability in comparison to genistein. Additionally, the structure of the substituent and its position on genistein influenced the type of mechanism involved in the transport of compounds through biological membranes. The PAMPA assay showed that the structure of glycoconjugates had a significant influence on the passive transport of the genistein synthetic derivatives through a biological membrane. Preferentially the glycoconjugates containing O -glycosidic bond were transported and the transport rate decreased as the carbon linker increased. For glycoconjugates, determination of their transport and metabolism through the Caco-2 membrane was not possible due to interaction with the membrane surface, probably by the change of compound structure caused by contact with the cells or degradation in medium. The intestinal absorption and metabolism of genistein and three derivatives, Ram-3, Ram′-3 and Ram-C-4α (Fig. 1), were tested in vivo in rats. We found that in comparison to genistein, glycoconjugates were metabolized more slowly and to a lesser extent. As part of the in vivo research, we performed analysis of compound levels in plasma samples after enzymatic hydrolysis, but in the collected samples, analytes were not observed. We hypothesize that glycoconjugates compounds bind plasma proteins and were removed from the sample. In conclusion, we show that O -functionalization of the natural, biologically active isoflavone genistein can affect biological activity, bioavailability, and the rate of compound metabolism. The position of the substituent, the length of the linker and the structure of sugar moieties provides a tool for the optimization of the derivative's biological properties. [ABSTRACT FROM AUTHOR]

In this paper, the interaction of genistein (GEN) and its four derivatives (GEN1-4) with bovine serum albumin (BSA) were investigated by ultraviolet-visible absorption spectra, fluorescence, synchronous fluorescence, three-dimensional fluorescence spectroscopy, circular dichroism and molecular docking techniques. The experimental results showed that the intrinsic fluorescence of BSA was quenched by genisteins and was due to the formation of a genisteins-BSA complex. The quenching constant, binding constants, binding sites, intermolecular distances and thermodynamic properties were calculated at 298 K, 306 K and 310 K. Site marker competitive experiments indicated that the binding site of genisteins to BSA was mainly located in subdomain IIA. The conformational investigation showed that the presence of 0020 genisteins led to changes in the secondary structure of BSA and induced the slight unfolding of protein polypeptides, which confirmed some micro-environmental and conformational changes of BSA molecules. Furthermore, the binding affinity decreased in the order GEN1 > GEN > GEN4 > GEN3 > GEN2, which revealed that different type and position of substituents of genistein significantly influenced the affinity of compounds to BSA. The number of hydroxyl groups on the ring A was the most important factor because increasing the hydroxyl groups on ring A clearly enhanced the binding affinity. However, trifluoromethylation did not much affect the affinity, alkylation, esterification and difluoromethylation slightly enhanced the binding affinity. The results obtained herein will provide valuable information about the pharmacokinetics at a molecular level and be a useful guideline for the further design of much more suitable genistein derivatives., (Copyright © 2017 John Wiley & Sons, Ltd.)