Natural Isoflavonoids Research Articles

Chitosan nanoparticles efficiently enhance the dispersibility, stability and selective antibacterial activity of insoluble isoflavonoids

Natural isoflavonoids have attracted much attention in the treatment of oral bacterial infections and other diseases due to their excellent antibacterial activity and safety. However, their poor water solubility, instability and low bioavailability seriously limited the practical application. In this study, licoricidin-loaded chitosan nanoparticles (LC-CSNPs) were synthesized by self-assembly for improving the dispersion of licoricidin (LC) and strengthening antibacterial and anti-biofilm performance. Compared to free LC, the minimum inhibitory concentration of LC-CSNPs against Streptococcus mutans decreased >2-fold to 26 μg/mL, and LC-CSNPs could ablate 70 % biofilms at this concentration. The enhanced antibacterial activity was mainly attributed to the spontaneous surface adsorption of LC-CSNPs on cell membranes through electrostatic interactions. More valuably, LC-CSNPs had no inhibitory effect on the growth of probiotic. Mechanism study indicated that LC-CSNPs altered the transmembrane potential to cause bacterial cells in a hyperpolarized state, generating ROS to cause cells damage and eventually apoptosis. This work demonstrated that the chitosan-based nanoparticles have great potential in enhancing the dispersibility and antibacterial activity of insoluble isoflavonoids, offering a promising therapeutic strategy for oral infections.

In vitro efficacy of isoflavonoids and terpenes against Leishmania (Leishmania) infantum and L. amazonensis

The main form of control of leishmaniasis is the treatment, however various side effects and poor efficacy are associated with presently available drugs. The investigation of bioactive natural products for new antileishmanial drugs is a valid approach. The present study reports the in vitro efficacy of natural isoflavonoids and terpenes against Leishmania infantum and L. amazonensis and their cytotoxicity against HepG2 cells. L. infantum and L. amazonensis promastigotes were exposed to the terpenes kaurenoic acid, xylopic acid, and (−)-α-bisabolol and to the isoflavonoids (−)-duartin and (3R)-claussequinone for antileishmanial activity and to cytotoxicity to HepG2 cells. The most effective substance against both L. infantum and L. amazonensis species was (3R)-claussequinone (IC50 = 3.21 μg/mL and 2.47 μg/mL, respectively) that disclosed low cytotoxicity against HepG2 cells (CC50 = 387.79 μg/mL). The efficacy of (3R)-claussequinone against intracellular amastigotes of L. infantum and the externalization of phosphatidylserine in promastigotes of this isoflavanoid were investigated by infection of Raw 264.7 macrophages and marking with Annexin V-FITC and propidium Iodide for flow cytometry analysis. The results for amastigotes showed that (3R)-claussequinone was able to reduce the rate of infection with IC50 = 4.61 μg/mL and did not alter the externalization of phosphatidylserine. In conclusion it is presently reported, for the first time, the striking antileishmanial activity of (3R)-claussequinone against L. infantum and L. amazonensis associated to low cytotoxicity. Furthermore, these results suggest that (3R)-claussequinone is a new hit aiming to develop new therapeutic alternatives.

Natural isoflavonoids in invasive cancer therapy: From bench to bedside.

Cancer is a public health problem worldwide, and one of the crucial steps within tumor progression is the invasion and metastasis of cancer cells, which are directly related to cancer-associated deaths in patients. Recognizing the molecular markers involved in invasion and metastasis is essential to find targeted therapies in cancer. Interestingly, about 50% of the discovered drugs used in chemotherapy have been obtained from natural sources such as plants, including isoflavonoids. Until now, most drugs are used in chemotherapy targeting proliferation and apoptosis-related molecules. Here, we review recent studies about the effect of isoflavonoids on molecular targets and signaling pathways related to invasion and metastasis in cancer cell cultures, in vivo assays, and clinical trials. This review also reports that glycitein, daidzein, and genistein are the isoflavonoids most studied in preclinical and clinical trials and displayed the most anticancer activity targeting invasion-related proteins such as MMP-2 and MMP-9 and also EMT-associated proteins. Therefore, the diversity of isoflavonoids is promising molecules to be used as chemotherapeutic in invasive cancer. In the future, more clinical trials are needed to validate the effectiveness of the various natural isoflavonoids in the treatment of invasive cancer.

Asymmetric one-pot transformation of isoflavones to pterocarpans and its application in phytoalexin synthesis

Phytoalexins have attracted much attention due to their health-promoting effects and their vital role in plant health during the last years. Especially the 6a-hydroxypterocarpans glyceollin I and glyceollin II, which may be isolated from stressed soy plants, possess a broad spectrum of bioactivities such as anticancer activity and beneficial contributions against western diseases by anti-oxidative and anti-cholesterolemic effects. Aiming for a catalytic asymmetric access to these natural products, we establish the asymmetric syntheses of the natural isoflavonoids (−)-variabilin, (−)-homopterocarpin, (−)-medicarpin, (−)-3,9-dihydroxypterocarpan, and (−)-vestitol by means of an asymmetric transfer hydrogenation (ATH) reaction. We successfully adapt this pathway to the first catalytic asymmetric total synthesis of (−)-glyceollin I and (−)-glyceollin II. This eight-step synthesis features an efficient one-pot transformation of a 2′-hydroxyl-substituted isoflavone to a virtually enantiopure pterocarpan by means of an ATH and a regioselective benzylic oxidation under aerobic conditions to afford the susceptible 6a-hydroxypterocarpan skeleton.

Reactivity of Condensed Isoflavone Derivatives for Hydrazine

Recyclization by hydrazine of furo[3,2-b]pyrano[2,3-f]chromen-4-ones, dipyrano[2,3-b:2,3-f]chromen4-ones, and pyrano[2,3-a]xanthen-4-ones derived from natural isoflavonoids and their analogs was studied. The reaction was shown to proceed selectively with opening of the chromone ring. Several substituted 4-arylpyrazoles containing furo[3,2-b]chromen-5-ol, pyrano[2,3-b]chromen-6-ol, and xanthen-8-ol fragments were synthesized.

Design and synthesis of chiral 2H-chromene-N-imidazolo-amino acid conjugates as aldose reductase inhibitors

Aldose reductase (ALR2) inhibitors provide a viable mode to fight against diabetic complications. ALR2 exhibit plasticity in the active site vicinities and possible shifts in the nearby two supporting alpha helices. Therefore, a novel series of amino acid conjugates of chromene-3-imidazoles (13–15) were designed and synthesized based on natural isoflavonoids. The compounds were identified on the basis of spectral (1H NMR, 13C NMR and MS) data and tested in vitro for ALR2 inhibitory activity with an IC50 value ranges from 0.031 ± 0.082 μM to 4.29 ± 0.55 μM. Our in silico and biochemical studies confirmed that 15e has the best inhibition activity among the synthesized compounds with a high selective index against the Aldehyde reductase (ALR1). Supplementation of 15e to STZ induced rats decreased the blood glucose levels and delayed the progression of cataract in a dose-dependent manner. The present study thus provides novel series of compounds with a promising inhibitor to prevent or delay the cataract progression.

Classification of natural estrogen-like isoflavonoids and diphenolics by QSAR tools.

This work reports a detailed study of the ability of linear and non-linear classification methods to estimate the estrogenic activities of a series of 55 natural estrogen-like isoflavonoid and diphenolic compounds. In doing so, we examined the use of linear discriminant analysis (LDA) and nonlinear support vector machines (SVMs) techniques along with feature selection algorithms. The structural characteristics of each of the studied compounds were calculated from the optimized molecular geometries. Both the LDA and SVMs models contain four descriptors, however, the SVMs model (total accuracy 89.1%) was found to be superior to the LDA model (total accuracy 80.0%). The analysis of molecular descriptors within our models provided essential insights towards a better understanding of the estrogenic mechanisms of natural estrogen-like phytoestrogens. Furthermore, the derived models can be applied in the future screening of other natural estrogen-like compounds.

Synthesis of 4-aryl-3-[2-hydroxy-4-(2-cytisin-12-ylethoxy)phenyl]pyrazoles

Recyclization of N 12-cytisinylethoxy derivatives of natural isoflavonoids and their analogs through the action of hydrazine hydrate was studied. A series of substituted 3-(2-hydroxyphenyl)-4-arylpyrazoles containing cytisine and pyrazole moieties were synthesized.

Comparative Study of the Antioxidative Potential of Common Natural Flavonoids and Isoflavonoids

) gets reduced to oxygen-derived free radi-cals such as superoxide, hydrogen peroxide, hydroxyl, andnitric oxide radicals during the normal physiological andmetabolic processes in the human body [4, 18]. Thesereactive oxygen species (ROS) generate oxidative stress inthe body [9] which affects cell proteins, lipids and carbohy-drates, leading to a number of physiological disorders, can-cer, cardiovascular disorders, and neurological disorders,and is involved in the process of aging [11]. Many plantsoften contain substantial amounts of antioxidants such asvitamin C and E, carotenoids, flavonoids and tannins toneutralize excess ROS. These natural compounds cantherefore be utilized to scavenge those free radicals fromthe human body. Antioxidants are widely used as food addi-tives to provide protection against oxidative degradation offoods. Since ancient times, spices added to different typesof food to improve flavors have also been recognized fortheir antioxidant capacities [10]. In order to prolong the stor-age stability of foods, synthetic antioxidants such as buty-lated hydroxytoluene and butylated hydroxyanisole areused for industrial processing. However, these compoundsare inappropriate for chronic human consumption.Flavonoids, plant secondary metabolites, are most com-monly known for their antioxidant activities. The antioxidantability of flavonoids is stronger than other commonly foundnatural products. Thus, consumers and food manufacturershave become interested in flavonoids for their possibleindustrial applications, medicinal properties, and especiallytheir putative role in the prevention of cancers, Parkinson’sdiseases, Alzheimer’s diseases, and cardiovascular dis-eases. Though the physiological evidence has not beenwell established on flavonoids and isoflavonoids, the bene-ficial effects of fruits, vegetables, tea, and red wine havebeen attributed to these groups of compounds. In recentdecades, strong interest has focused on screening essen-tial oils and various plant extracts for natural antioxidantsbecause of their good antioxidant properties. The com-pounds showing high activity to scavenge free radical couldbe pharmaceutically crucial to develop as a drug against

Reaction of natural isoflavonoids and their analogs with hydroxylamine

Recyclization of the chromone ring in several natural isoflavonoids and their analogs by reaction with hydroxylamine was studied. It has been found that the most suitable base for carrying out the reaction is N-methylmorpholine. Several derivatives of 4-aryl-5-(2-hydroxyphenyl)isoxazole were synthesized.

Reaction of analogs of natural isoflavonoids with amidines

Recyclization of the chromone ring in a series of analogs of natural isoflavonoids by reaction with amidines was studied.

Erybraedin C and bitucarpin A, two structurally related pterocarpans purified from Bituminaria bituminosa, induced apoptosis in human colon adenocarcinoma cell lines MMR- and p53-proficient and -deficient in a dose-, time-, and structure-dependent fashion

Pterocarpans, the second group of natural isoflavonoids, have received considerable interest on account of their medicinal properties. These drugs are employed as antitoxins, but display antifungal, antiviral and antibacterial properties as well. Erybraedin C and bitucarpin A are two new structurally related pterocarpans recently purified and characterized. Bitucarpin A differs from erybraedin C for the absence of a prenyl group in 5′ position and the presence of a methoxylate hydroxyl group in 7, 4′ positions. These compounds proved not to be clastogens in human lymphocytes per se but displayed anticlastogenic activity against mytomicin C and bleomycin C. Here we extended the study of their antiproliferative and apoptosis-inducing mechanism on human cell lines. Two human adenocarcinoma cell lines, LoVo and HT29, as examples of slow-growing solid tumors, proficient and deficient in mismatch repair system (MMR), p53 and Bcl-2, were used to evaluate the cytotoxicity of the drugs and their effects on the cell cycle, measured by flow cytometry. Erybraedin C similarly affects the survival of HT29 (MMR +/+, p53 −/− and Bcl-2 +/+) and LoVo (MMR −/−, p53 +/+ and Bcl-2 −/−) cells (LD 50: 1.94 and 1.73 μg/ml, respectively). By contrast, bitucarpin A exhibits a differential cytotoxicity in the cell lines (LD 50: 6.00 μg/ml, HT29, and 1.84 μg/ml, LoVo). The cell cycle distributions of the LoVo and HT29 cells treated with erybraedin C lacked a specific checkpoint arrest, whereas they underwent a characteristic sub-G 1 peak, time- and drug-concentration dependent. So that apoptotic process induced by erybraedin C in both adenocarcinoma cell lines is independent of cell cycle arrest and of phenotypic status of the cells as well. By contrast, bitucarpin A affects cell cycle progression on both cell lines, inducing a transient block in G 0/G 1 along 24–96 h, and induces apoptosis with a cell density and treatment time dependency. Similar results were obtained with the positive control drug etoposide. The programmed cellular death on human adenocarcinoma cell lines may be efficiently activated, via a topoisomerase II poison pattern, by erybraedin C, the drug containing regio-specific hydroxyl and prenyl groups. The apoptotic effect induced by the methoxylated bitucarpin A proved to be conditioned by cell density and required higher dose (5-fold-LD 50) and longer treatment time. The present study provides evidences that erybraedin C may act as a potent growth inhibitory compound, at low and high cell density, comparable to other clinically important antineoplastic natural drugs including etoposide, on human colon adenocarcinoma cells. Bitucarpin A proved less active because it was conditioned by cell density effect, but this finding may represent a clinical advantage against early micrometastatic diseases.

Synthesis of analogs of natural isoflavonoids containing phloroglucinol

Analogs of the natural isoflavonoids biochanin A and orobol were synthesized. Alkylation involving phenolic hydroxyls and the chromone ring was studied.

Basicity constants of natural isoflavonoids

The basicities (pKBH+) of 13 natural isoflavones have been determined spectrophotometrically in sulfuric acid solutions. It has been shown that the change of basicity in this series of compounds depends on the geometry of the molecules and on intramolecular effects.

Inhibition of Rat Heart Phosphodiesterase by some Rotenoids and Isoflavonoids

Series of natural and semisynthetic rotenoids and isoflavonoids were studied for their inhibitory activity on cyclic AMP phosphodiesterase (PDE) in rat heart. Some of the compounds showed higher inhibitory activity than that of the most potent flavonoids. The chemical transformation of the starting natural compounds failed to increase their inhibitory potency. PDE inhibition was of a noncompetitive type.

Advances in the chemistry of natural isoflavonoids

Advances in the chemistry of natural isoflavonoids

Synthesis of sophorol, violanone, lonchocarpan, claussequinone, philenopteran, leiocalycin, and some other natural isoflavonoids by the oxidative rearrangement of chalcones with thallium(III) nitrate

Isoflavones are conveniently prepared by the oxidative rearrangement of 2′-hydroxy- or 2′-acetoxy-chalcones with thallium(III) nitrate in methanol into 1-(2-hydroxyphenyl)-3,3-dimethoxy-2-phenylpropan-1-ones [e.g.(46)] followed by cyclisation, and the following natural isoflavonoids were synthesised in this way: the isoflavanones sophorol (49) and violanone (68), the isoflavans vestitol (57), duratin (58), mucronulatol (59), laxifloran (60), and Ionchocarpan (61), the isoflavan quinones mucroquinone (66) and claussequinone (67), the pterocarpans philenopteran (69), leiocalycin (54), and 2-hydroxy-3-methoxy-8,9-methylenedioxy-6a,11a-dihydropterocarpan (56).Acid catalysed cyclisation of 1-(2-hydroxy-4-methoxyphenyl)-2-(2-hydroxy-4,5-methylenedioxyphenyl)-3,3-dimethoxypropan-1-one (48) gave no isoflavone but the two tetracyclic compounds, (53)(a derivative of 2-methoxypterocarp-6-ene) and (52)(a benzofuro[2,3-b][1]benzopyran).Claussequinone (67) was rapidly formed by autoxidation of its hydroquinone precursor (64), suggesting that oxidation may also have occurred during the isolation of the metabolite.