Isoflavone Derivatives Research Articles

Halogenated Flavones and Isoflavones: A State-of-Art on their Synthesis.

Flavonoid is a family of compounds present in the everyday consumption plants and fruits, contributing to a balanced diet and beneficial health effects. Being a scaffold for new drugs and presenting a wide range of applicability in the treatment of illnesses give them also an impact in medicine. Among the several types of flavonoids, flavone and isoflavone derivatives can be highlighted due to their prevalence in nature and biological activities already established. The standard synthetic route to obtain both halogenated flavones and isoflavones is through the use of already halogenated starting materials. Halogenation of the flavone and isoflavone core is less common because it is more complicated and involves some selectivity issues. Considering the importance of these flavonoids, we aim to present the main and more recent synthetic approaches towards their halogenation. The most prominent methodologies for the synthesis of halogenated flavones and isoflavones were reviewed. A careful survey of the reported data, using mainly the Scopus database and halogenation, flavones and isoflavones as keywords, was conducted. Herein, a review is provided on the latest and more efficient halogenation protocols of flavones and isoflavones. Selective halogenation and the greener methodologies, including enzymatic and microbial halogenations, were reported. Nevertheless, some interesting protocols that allowed the synthesis of halogenated flavone and isoflavone derivatives in specific positions using halogenated reagents are also summarized. Halogenated flavones and isoflavones have risen as noticeable structures; however, most of the time, the synthetic procedures involve toxic reagents and harsh reaction conditions. Therefore, the development of new synthetic routes with low environmental impact is desirable.

Design, synthesis and the structure-activity relationship of agonists targeting on the ALDH2 catalytic tunnel

ALDH2, a key enzyme in the alcohol metabolism process, detoxifies several kinds of toxic small molecular aldehydes, which induce severe organ damages. The development of novel Alda-1 type ALDH2 activators was mostly relied on HTS but not rational design so far. To clarify the structure–activity relationship (SAR) of the skeleton of Alda-1 analogs by synthesis of the least number of analogs, we prepared 31 Alda-1 analogs and 3 isoflavone derivatives and evaluated for their ALDH2-activating activity. Among these, the ALDH2-activating activity of mono-halogen-substituted (Cl and Br) N-piperonylbenzamides 3b and 3 k, and non-aromatic amides 8a-8c, were 1.5–2.1 folds higher than that of Alda-1 at 20 μM. The relationship between binding affinity in computer aided molecular docking model and the ALDH2-activating activity assays were clarified as follows: for Alda-1 analogs, with the formation of halogen bonds, the enzyme-activating activity was found to follow a specific regression curve within the range between −5 kcal/mol and −4 kcal/mol. For isoflavone derivatives, the basic moiety on the B ring enhance the activating activity. These results provide a new direction of utilizing computer-aided modeling to design novel ALDH2 agonists in the future.

Screening, Synthesis, and Evaluation of Novel Isoflavone Derivatives as Inhibitors of Human Golgi β-Galactosidase.

The genes GLB1 and GALC encode GLB1 isoform 1 and galactocerebrosidase, respectively, which exhibit β-galactosidase activity in human lysosomes. GLB1 isoform 1 has been reported to play roles in rare lysosomal storage diseases. Further, its β-galactosidase activity is the most widely used biomarker of senescent and aging cells; hence, it is called senescence-associated β-galactosidase. Galactocerebrosidase plays roles in Krabbe disease. We previously reported a novel β-galactosidase activity in the Golgi apparatus of human cells; however, the protein responsible for this activity could not be identified. Inhibitor-derived chemical probes can serve as powerful tools to identify the responsible protein. In this study, we first constructed a cell-based high-throughput screening (HTS) system for Golgi β-galactosidase inhibitors, and then screened inhibitors from two compound libraries using the HTS system, in vitro assay, and cytotoxicity assay. An isoflavone derivative was identified among the final Golgi β-galactosidase inhibitor compound hits. Molecular docking simulations were performed to redesign the isoflavone derivative into a more potent inhibitor, and six designed derivatives were then synthesized. One of the derivatives, ARM07, exhibited potent inhibitory activity against β-galactosidase, with an IC50 value of 14.8 µM and competitive inhibition with Ki value of 13.3 µM. Furthermore, the in vitro and cellular inhibitory activities of ARM07 exceeded those of deoxygalactonojirimycin. ARM07 may contribute to the development of affinity-based chemical probes to identify the protein responsible for the newly discovered Golgi β-galactosidase activity. The therapeutic relevance of ARM07 against lysosomal storage diseases and its effect on senescent cells should be evaluated further.

Antimicrobial Isoflavones and Derivatives from Erythrina (Fabaceae): Structure Activity Perspective (Sar & Qsar) on Experimental and Mined Values Against Staphylococcus aureus

Prenylated (iso)flavonoids, -flavans and pterocarpans from taxa in Erythrina are repeatedly flagged as potent antimicrobial compounds. In the current study, bark from E. lysistemon was extracted and seven isoflavone derivatives were purified: erybraedin A (1), phaseollidin (2), abyssinone V-4′ methyl ether (3), eryzerin C (4), alpumisoflavone (5), cristacarpin (6) and lysisteisoflavone (7). Minimum inhibition concentration (MIC) values were determined against a range of species of bacteria (skin pathogens), then values for another 67 derivatives from Erythrina, only against Staphylococcus aureus, were mined from the literature. Of the seven isolates, MIC values widely ranged from 1–600 μg/mL, with no obvious pattern of selectivity for Gram-types. Nevertheless, using the mined and experimentally determined values against S. aureus, Klekota-Roth fragments (Structure Activity Relationship: SAR) were determined then used as molecular descriptors to make a ‘decision tree’ based on structural characters inspired by the classes of antimicrobial potency (classes A-D). Furthermore, to make quantitative predictions of MIC values (Quantitative SAR: QSAR) ‘pace regression’ was utilized and validated (R² = 0.778, Q² = 0.727 and P² = 0.555). Evidently, the position and degree of prenylation is important; however, the presence of hydroxyl groups at positions 5 and 7 in ring A and 4′ in ring B is associated with lower MIC values. While antimicrobial results continue to validate the traditional use of E. lysistemon extracts (or Erythrina generally) in therapeutic applications consistent with anti-infection, it is surprising that this class of compound is not being utilized more often in general industry applications, such as food or cosmetic preservation, or in topical antimicrobial creams. Prenylated (iso)flavonoids are derived from several other Genera, such as Dorstenia (Moraceae), Ficus (Moraceae), Glycyrrhiza (Fabaceae), Paulownia (Lamiales) or Pomifera (Moraceae).

An isoflavone derivative potently inhibits the angiogenesis and progression of triple-negative breast cancer by targeting the MTA2/SerRS/VEGFA pathway.

Objective: Angiogenesis plays a vital role in tumor growth and metastasis. Here, we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A (VEGFA ) at the transcriptional level to treat triple-negative breast cancer (TNBC).Methods: We used a cell-based seryl tRNA synthetase (SerRS) promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS, a potent transcriptional repressor of VEGFA. The levels of SerRS and VEGFA were examined by quantitative RT-PCR (qRT-PCR), western blotting, and/or ELISAs in TNBC cells after candidate molecule administration. Zebrafish, the Matrigel plug angiogenesis assay in mice, the TNBC allograft, and xenograft mouse models were used to evaluate the in vivo anti-angiogenic and anti-cancer activities. Furthermore, the potential direct targets of the candidates were identified by proteomics and biochemical studies.Results: We found the most active compound was 3-(4-methoxyphenyl) quinolin-4(1H)-one (MEQ), an isoflavone derivative. In TNBC cells, MEQ treatment resulted in increased SerRS mRNA (P < 0.001) and protein levels and downregulated VEGFA production. Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ. MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice, resulting in inhibited tumor growth and prolonged overall survival (P < 0.05). Finally, we found that MEQ regulated SerRS transcription by interacting with MTA2 (Metastasis Associated 1 Family Member 2).Conclusions: Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target, and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.

Suppressive Effects of GSS on Lipopolysaccharide-Induced Endothelial Cell Injury and ALI via TNF-αand IL-6

Background. Under septic conditions, LPS induced lung vascular endothelial cell (EC) injury, and the release of inflammatory mediator launches and aggravates acute lung injury (ALI). There are no effective therapeutic options for ALI. Genistein-3′-sodium sulfonate (GSS) is a derivative of native soy isoflavone, which exhibits neuroprotective effects via its antiapoptosis property. However, whether GSS protect against sepsis-induced EC injury and release of inflammatory mediators has not been determined. In this study, we found that GSS not only downregulated the levels of TNF-α and IL-6 in the lung and serum of mice in vivo but also inhibited the expression and secretion of TNF-α and IL-6 in ECs. Importantly, we also found that GSS blocked LPS-induced TNF-α and IL-6 expression in ECs via the Myd88/NF-κB signaling pathway. Taken together, our results demonstrated that GSS might be a promising candidate for sepsis-induced ALI via its regulating effects on inflammatory response in lung ECs.

Genistein-3'-sodium sulphonate protects against lipopolysaccharide-induced lung vascular endothelial cell apoptosis and acute lung injury via BCL-2 signalling.

Under septic conditions, Lipopolysaccharide (LPS)‐induced apoptosis of lung vascular endothelial cells (ECs) triggers and aggravates acute lung injury (ALI), which so far has no effective therapeutic options. Genistein‐3′‐sodium sulphonate (GSS) is a derivative of native soy isoflavone, which has neuro‐protective effects through its anti‐apoptotic property. However, whether GSS protects against sepsis‐induced lung vascular endothelial cell apoptosis and ALI has not been determined. In this study, we found that LPS‐induced Myd88/NF‐κB/BCL‐2 signalling pathway activation and subsequent EC apoptosis were effectively down‐regulated by GSS in vitro. Furthermore, GSS not only reversed the sepsis‐induced BCL‐2 changes in expression in mouse lungs but also blocked sepsis‐associated lung vascular barrier disruption and ALI in vivo. Taken together, our results demonstrated that GSS might be a promising candidate for sepsis‐induced ALI via its regulating effects on Myd88/NF‐κB/BCL‐2 signalling in lung ECs.

Synthesis of Isoflavones by Tandem Demethylation and Ring-Opening/Cyclization of Methoxybenzoylbenzofurans.

The unexpected conversion of benzoylbenzofurans into isoflavones through an intramolecular cascade that involves deprotection and ring-opening/cyclization is described. This was discovered in an investigation of the possible transformation of benzoylbenzofurans into coumaronochromones. This route affords isoflavones in two major steps from acetophenones and benzoquinones. The transformation was validated by synthesizing differently substituted isoflavone derivatives and further applied to a concise synthesis of a potential anticancer lead compound, glaziovianin A (1).

Two New Isoflavones from Phlomis betonicoides and Their Antioxidant Activity

Two new isoflavones derivatives, 8,4′-dimethoxy-7-(3-hydroxypropyl)-isoflavone (1) and 8,4′-dimethoxy-7-(3-hydroxypropanoyl)-isoflavone (2), were isolated from the roots of Phlomis betonicoides. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1 and 2 were also tested for the antioxidant activity, and they show good antioxidant activity with an IC50 value of 3.8 and 3.6 μg/mL, respectively.

The isoflavone puerarin induces Foxp3+ regulatory T cells by augmenting retinoic acid production, thereby inducing mucosal immune tolerance in a murine food allergy model

The disruption of intestinal mucosal immune tolerance can lead to the development of intestinal immune diseases such as food allergy (FA). Regulatory T cells (Tregs) in the mucosa play a critical role in maintaining peripheral immune tolerance in the intestine, and retinoic acid (RA) is absolutely required for the induction of Tregs. We have previously reported that kakkonto, a traditional Japanese herbal medicine, suppresses FA in a murine FA model due to the induction of Tregs in the colonic mucosa. However, the precise molecular mechanisms underlying the induction of Tregs remain unclear. Puerarin, an isoflavone derivative, is a major constituent of kakkonto. Thus, we investigated the effect of puerarin on the induction of Tregs. BALB/c mice were systemically sensitized and then orally challenged with ovalbumin (OVA) as an FA model. Puerarin treatment suppressed the development of allergic diarrhea in FA mice. The gene expression levels of IL-4 and mast cell protease I (mMCP-1) were significantly upregulated in the proximal colon of FA mice but were reduced by puerarin. The proportions of Foxp3+CD4+ cells and CD103+CD11c+ dendritic cells (DCs) were significantly higher among the colonic lamina propria (cLP) cells of puerarin-treated FA mice than among those of untreated FA mice. The gene expression of Aldh1a1, an RA synthesis enzyme, in colonic epithelial cells (CECs) was significantly higher in the puerarin-treated FA mouse colon than in the untreated FA mouse colon. In addition, the preventive effect of puerarin was suppressed in the FA model by pretreatment with LE540, an RA receptor (RAR) antagonist. The induction of Foxp3+CD4+ cells and CD103+CD11c+ DCs by puerarin was reduced by pretreatment with LE540. The present findings indicate that the augmentation of RA production in CECs induced by puerarin enhances the induction of Tregs and suppresses the development of FA in a mouse model. Thus, a natural enhancer of RA production, such as puerarin, has the potential to treat immune diseases attributed to Treg deficiency.

Flavone norartocarpetin and isoflavone 2′-hydroxygenistein: A spectroscopic study for structure, electronic property and antioxidant potential using DFT (Density functional theory)

Flavone and isoflavone derivatives have drawn much attention because of their antioxidant radical scavenging capacity. Based on computational methods, we now present the antioxidant potential results of flavone norartocarpetin (1) and isoflavone 2′-hydroxygenistein (2). The optimized structures of the neutral and radical forms have been carried out by DFT-B3LYP method with the 6-311++G (d,p) basis set. From the findings and thermodynamic point of view, ring B system of either flavone or isoflavone is considered as an active centre in facilitating antioxidant reactions. Antioxidant activities are mostly driven by the O–H bond dissociation enthalpy (BDE) following hydrogen atom transfer (HAT) mechanism. In all studied environments, the lowest BDE values are found in 4′-OH and 2′-OH of compounds 1-2, respectively. Isoflavone 2 possesses a higher antioxidant capacity than that of flavone 1. Of extensive analysis, intramolecular hydrogen bonds and solvents not only greatly influence on antioxidant aspect but also directly affect the structural properties, especially spectroscopic outcomes.

Anti-Inflammatory and Antiproliferative Prenylated Isoflavone Derivatives from the Fruits of Ficus carica.

Ficus carica is an Asian species of flowering plant belonging to the genus Ficus of the family Moraceae, native to Western Asia and the Middle East. Its fruits, usually known as common fig or fig, have been consumed as a very popular health-promoting fruit worldwide since ancient times. To investigate the potential health-promoting chemical constituents of the fruits of F. carica, a systematic phytochemical study on its fruits was therefore carried out. In our study, four new structurally diverse prenylated isoflavone derivatives, ficucaricones A-D (1-4), along with 12 known analogues (5-16) were separated from the fruits of F. carica. Their chemical structures were ambiguously elucidated based on extensive spectroscopic methods. The anti-inflammatory effects and antiproliferative activities of these isolated prenylated isoflavone derivatives were tested. Prenylated isoflavone derivatives (1-16) displayed remarkable inhibitory effects against nitric oxide (NO) production with the IC50 values ranging from 0.89 ± 0.05 to 8.49 ± 0.18 μM, comparable to that of the positive control (hydrocortisone). Furthermore, compounds 1-16 also exhibited pronounced antiproliferative activities against diverse human cancer cell lines in vitro, holding the IC50 values ranging from 0.18 ± 0.03 to 18.76 ± 0.09 μM. These findings indicate that regular consumption of the fruits of F. carica may help to prevent the occurrence of inflammatory diseases and tumors. Moreover, the isolation and characterization of these prenylated isoflavone derivatives possessing remarkable anti-inflammatory effects and antiproliferative activities could be meaningful to the discovery of new anti-inflammatory and antitumor agents.

Phytochemical Analysis and Total Antioxidant Capacity of Rhizome, Above-Ground Vegetative Parts and Flower of Three Iris Species.

This study was aimed at investigating the phytochemical composition and antioxidant capacity of rhizomes, above-ground vegetative parts and flowers of three Iris species: Iris humilis Georgi, Iris pumila L. and Iris variegata L. UHPLC-Orbitrap MS analysis was used for determination of phytochemical profile. Total pigments, phenolics, flavonoids, soluble sugars and starch content as well as ABTS antioxidant capacity were also determined. In total, 52 phenolics compounds were identified with 9 compounds (derivatives of iriflophenone, apigenin C-glycosides, luteolin O-glycoside, isoflavones derivatives of iristectorigenin, dichotomitin, nigracin and irilone) never reported before in Iris spp. Differences in phenolic composition profile, pigments, soluble sugar, starch, total phenolics and flavonoids content and total antioxidant capacity were found among Iris species and different part of plants. Significant correlation between total phenolic content and antioxidant capacity was determined. The obtained results are comparable with those obtained for medical plants. These findings could be useful for fingerprinting characterization of Iris species and estimation of possible use in pharmaceutical industries.

Discovery of 3-Amino-2-Hydroxypropoxyisoflavone Derivatives as Potential Anti-HCV Agents.

Synthesis and anti-hepatitis C virus (anti-HCV) effects of certain 3-amino-2-hydroxy-propoxy isoflavone derivatives, 6a–i, were described. The known 3-(3,4-dimethoxyphenyl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (5) was reacted with substituted amines to give the desired isoflavone derivatives, 6a–i. Among them, 7-{3-[(3,4-dimethoxy-phenethyl)amino]-2-hydroxypropoxy}-3-(3,4-dimethoxyphenyl)-4H-chromen-4-one (6b) was the most active, exhibiting approximately 2-fold higher anti-HCV effects than standard antiviral drug ribavirin (EC50 of 6.53 vs. 13.16 μM). In addition, compound 6b was less cytotoxic than ribavirin. The selectivity index (SI) of 6b is approximately 2.6-fold higher than ribavirin. The compounds 6e, 6h, and 6i were also found to possess higher anti-HCV effects than ribavirin. Compound 6b was found to inhibit the HCV RNA expression in Ava5 cells in a dose-dependent manner; furthermore, we found that the antiviral mechanism of compounds 6b, 6e, 6h, and 6i gave rise to induction of HO-1 expression. With the HO-1 promoter-based analysis, we found compounds 6b, 6e, 6h, and 6i induced HO-1 expression through increasing Nrf-2 binding activity. Taken together, compound 6b may serve as a potential lead compound for developing novel anti-HCV agents.

Structure-guided design and synthesis of isoflavone analogs of GW4064 with potent lipid accumulation inhibitory activities

Our group has previously reported a series of isoflavone derivatives with antidyslipidemic activity. With this background, a series of isoflavone analogs of GW4064 were designed, synthesized and evaluated the lipid-lowering activity of analogs. As a result, most of compounds significantly reduced the lipid accumulation in 3T3-L1 adipocytes and four of them (10a, 11, 15c and 15d) showed stronger inhibitory than GW4064. The most potent compound 15d exhibited promising agonistic activity for FXR in a cell-based luciferase reporter assay. Meanwhile, 15d up-regulated FXR, SHP and BSEP gene expression and down-regulated the mRNA expression of lipogenesis gene SREBP-1c. Besides, an improved safety profile of 15d was also observed in a HepG2 cytotoxicity assay compared with GW4064. The obtained biological results were further confirmed by a molecular docking study showing that 15d fitted well in the binding pocket of FXR and interacted with some key residues simultaneously.

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.

Polymeric solvent engineering for gram/liter scale production of a water-insoluble isoflavone derivative, (S)-equol.

A potent phytoestrogen, (S)-equol, is a promising isoflavone derivative drawing our great attention owing to its various biological and clinical benefits. Through selective activation of the estrogen receptor ERβ or androgen receptor, (S)-equol reduces menopausal symptoms, osteoporosis, skin aging, hair loss, and incidence of prostate or ovarian cancers without adverse effects. Traditional biosynthesis of (S)-equol exploited non-productive natural equol-producing anaerobic bacteria that mainly belong to Coriobacteriaceae isolated from human intestine. Recently, we developed a recombinant Escherichia coli strain which could convert daidzein into (S)-equol effectively under an aerobic condition. However, the yield was limited up to about the 200mg/L level due to unknown reasons. In this study, we identified that the bottleneck of the limited production was the low solubility of isoflavone (i.e., 2.4mg/L) in the reaction medium. In order to solve the solubility problem without harmful effect to the whole-cell catalyst, we applied commercial hydrophilic polymers (HPs) and a polar aprotic co-solvent in the reaction medium. Among the examined water-soluble polymers, polyvinylpyrrolidone (PVP)-40k was verified as the most promising supplement which increased daidzein solubility by 40 times and (S)-equol yield up to 1.22g/L, the highest ever reported and the first g/L level biotransformation. Furthermore, PVP-40k was verified to significantly increase the solubilities of other water-insoluble natural polyphenols in aqueous solution. We suggest that addition of both HP and polar aprotic solvent in the reaction mixture is a powerful alternative to enhance production of polyphenolic chemicals rather than screening appropriate organic solvents for whole-cell catalysis of polyphenols.

Preparation, spectral and thermal properties of new Isoflavone derivatives: mesomorphic properties and DFT studies

ABSTRACTThe four new homologous series of symmetric Isoflavon dimers were synthesised using varied alkyl/aryl diamines in linear sense. The chemical structures of the molecules were characterised by IR, NMR and CHNS analysis. Further, Liquid crystalline properties were verified using the combination of differential scanning calorimetry (DSC) and polarised optical microscope (POM). The molecular systems studied here reveal that LC property depends on the length of the middle connecting diamine spacer along with terminal alkyl spacer. The lower members favour to exhibit smectic A phase, whereas higher members exhibit nematic mesophase. The nature of LC property behaviours is supported by molecular geometries studied by DFT calculations.

A sorafenib-sparing effect in the treatment of thyroid carcinoma cells attained by co-treatment with a novel isoflavone derivative and 1,25 dihydroxyvitamin D3

BackgroundSorafenib improves progression-free survival in patients with progressive radioactive iodine-refractory differentiated thyroid carcinoma, but causes severe side effects. Estrogens may accelerate thyroid carcinoma cell growth. Our group recently reported that isoflavone derivative 7-(O)-carboxymethyl daidzein conjugated to N-t-boc-hexylenediamine (cD-tboc), a novel anti-estrogenic compound, retards the growth of both thyroid carcinoma cell lines and cultured human carcinoma cells. Vitamin D receptor (VDR) is expressed in malignant cells and responds to 1,25 dihydroxyvitamin D3 (1.25D) by decreased proliferative activity in vitro. The purpose of this study was to examine the effects of vitamin D metabolites (VDM) on the expression of estrogen receptors (ERs), VDR, and 1OHase mRNA, and to evaluate the inhibitory effect of low doses of sorafenib in combination with cDtboc and VDM on cell proliferation in cultured human papillary thyroid carcinoma (PTC). MethodsIn 19 cultured PTC specimens and 19 normal thyroid specimens, harvested during thyroidectomies from the same patients, expression levels of ERα, ERβ, VDR, and 1 alpha-hydroxylase (1OHase) mRNA (by quantitative real-time PCR) were determined at baseline and after treatment with VMD. Cell proliferation was determined by measurement of 3[H] thymidine incorporation after treatment with sorafenib alone, sorafenib with added 1.25D or cD-tboc, and sorafenib with both 1.25D and cD-tboc added. Results1,25D increased mRNA expression of all tested genes in the malignant and normal thyroid cells, while the ERα mRNA of the normal cells was unaffected. 1.25D dose-dependently inhibited cell proliferation in the malignant cells. The inhibitory effect of sorafenib on cell proliferation in the malignant cells was amplified after the addition of cDtboc and 1.25D, such that the maximal inhibition was not only greater, but also had been attained at a 10-fold lower concentration of sorafenib (20 μg/ml). This inhibition was similar to that of the generally used concentration of sorafenib (200 μg/ml) alone. ConclusionsThe demonstration that low concentrations of cDtboc and 1.25D markedly amplify the inhibitory effect of sorafenib on the growth of human PTC supports the use of a 10-fold lower concentration of sorafenib. The findings may promote a new combination treatment for progressive radioactive iodine-refractory PTC.

Anti-inflammatory isoflavones and isoflavanones from the roots of Pongamia pinnata (L.) Pierre

A phytochemical study on the roots of Pongamia pinnata afforded five new isoflavone and isoflavanone derivatives (1–5), including two previously undescribed phenylisoflavones possessing an 1,2-oxetane ring, along with 21 known compounds (6–26) among which compound 18 is the first time to be isolated from nature. The structures of the isolated compounds were determined on the basis of 1D, 2D NMR, and HRESIMS. The absolute configurations of the compounds were assigned via analysis of the specific rotations and circular dichroism (CD) spectra, as well as by comparison of the calculated and experimental electronic circular dichroism (ECD) data. All the isolated compounds were evaluated for their inhibitory effects on NO production in LPS-stimulated BV-2 microglial cells. Twelve compounds exhibited different levels of inhibitory effects against NO production, and compound 1 showed the best activity with an IC50 value at 9.0 μM.