benzofurans and coumestan

Traditional Chinese medicines (TCM) have been proven to prevent osteoporosis, but their clinical applications are not widely recognized due to their complicated ingredients. Psoralidin, a prenylated coumestan, has been reported to prevent bone loss of ovariectomized rats, but detailed mechanisms are still not clear. In current study, we found that both psoralidin and coumestrol promoted osteoblast proliferation and differentiation, as evidenced by improvements in cell proliferation and alkaline phosphatase activity; increased formation of ALP colonies and calcified nodules; enhanced secretion of collagen-I, BMP-2, osteocalcin and osteopontin; and stimulation of the expression of IGF-1, β-catenin, Runx-2, Osterix, and OPG, as well as the mRNA ratio of OPG/RANKL, while significantly decreasing the expression of RANKL. In addition, both psoralidin and coumestrol inhibited osteoclast formation and osteoclastic bone resorption, as demonstrated by the lower tartrate-resistant acid phosphatase activity and smaller area, with fewer resorption pits formed. Interestingly, psoralidin showed much stronger effects than coumestrol at enhancing osteoblast proliferation/differentiation or inhibiting osteoclast differentiation and bone resorption. Moreover, we found that both psoralidin and coumestrol suppressed COX-2 and ROS production in rat osteoblastic calvarias cells, and psoralidin showed stronger effects than coumestrol. Furthermore, we detected that by blocking estrogen receptors with ICI 182.780 (an estrogen receptor antagonist), the osteoprotective effects of psoralidin and coumestrol were also blocked. Our findings demonstrated that psoralidin and coumestrol exert their bone-protective effects by enhancing bone formation of osteoblasts and inhibiting bone resorption of osteoclasts. These roles might be mediated by their antioxidant activity and transduced through estrogen receptor signaling.

Topics: Alkaline Phosphatase; Animals; Benzofurans; Bone Resorption; Cell Differentiation; Cell Proliferation; Coumarins; Dose-Response Relationship, Drug; Osteoclasts; Osteogenesis; Osteoporosis; Prenylation; Rats; Rats, Sprague-Dawley; Skull

A highly efficient synthetic route to pterocarpenes and coumestans is described. BCl3-mediated dehydrative cyclization of 1,3-diaryloxyacetones under mild conditions permitted regioselective ring closure to afford 3-((2-iodoaryloxy)methyl)benzofurans which were converted to the corresponding pterocarpenes by Pd-catalyzed intramolecular direct arylation. The subsequent benzylic oxidation led to coumestans. This sequence was applied to the formal syntheses of coumestrol and the proposed structure of plicadin as well as total syntheses of flemichapparins B and C.

Topics: Benzofurans; Chemistry Techniques, Synthetic; Coumarins; Stereoisomerism

A novel biological activity of psoralidin as an agonist for both estrogen receptor (ER)α and ERβ agonist has been demonstrated in our study. Psoralidin has been characterized as a full ER agonist, which activates the classical ER-signaling pathway in both ER-positive human breast and endometrial cell lines as well as non-human cultured cells transiently expressing either ERα or ERβ. The estrogenic activity was determined using the relative expression levels of either reporter or the endogenous genes dependent on the agonist-bound ER to the estrogen response element (ERE). Psoralidin at 10 μM was able to induce the maximum reporter gene expression corresponding to that of E2-treated cells and such activation of the ERE-reporter gene by psoralidin was completely abolished by the cotreatment of a pure ER antagonist, implying that the biological activities of psoralidin are mediated by ER. Psoralidin was also able to induce the endogenous estrogen-responsive gene, pS2, in human breast cancer cells MCF-7. It was observed that activation of the classical ER-signaling pathway by psoralidin is mediated via induction of ER conformation by psoralidin and direct binding of the psoralidin-ER complex to the EREs present in the promoter region of estrogen-responsive genes, as shown by chromatin immunoprecipitation assay results. Finally, molecular docking of psoralidin to the ligand binding pocket of the ERα showed that psoralidin is able to mimic the binding interactions of E2, and thus, it could act as an ER agonist in the cellular environment.

Topics: Benzofurans; Binding Sites; Cell Line; Cell Proliferation; Coumarins; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Humans; Molecular Docking Simulation; Protein Binding; Protein Structure, Tertiary; Psoralea; Receptors, Estrogen; Signal Transduction

Coumestan is a natural tetracycle with a C═C bond shared by a coumarin moiety and a benzofuran moiety. In addition to the function of the hydroxyl group on the antioxidant activity of coumestan, it is worth exploring the influence of the oxygen-abundant scaffold on the antioxidant activity as well. In this work, seven coumestans containing electron-withdrawing and electron-donating groups were synthesized to evaluate the abilities to trap 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(•+)), 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and galvinoxyl radical, respectively, and to inhibit the oxidations of DNA mediated by (•)OH, Cu(2+)/glutathione (GSH), and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH), respectively. It was found that all of the coumestans used herein can quench the aforementioned radicals and can inhibit (•)OH-, Cu(2+)/GSH-, and AAPH-induced oxidations of DNA. In particular, substituent-free coumestan exhibits higher ability to quench DPPH and to inhibit AAPH-induced oxidation of DNA than Trolox. In addition, nonsubstituted coumestan shows a similar ability to inhibit (•)OH- and Cu(2+)/GSH-induced oxidations of DNA relative to that of Trolox. The antioxidant effectiveness of the coumestan can be attributed to the lactone in the coumarin moiety and, therefore, a hydroxyl group may not be a necessary functional group for coumestan to be an antioxidant.

Topics: Amidines; Antioxidants; Benzofurans; Biphenyl Compounds; Coumarins; DNA; Glutathione; Hydroxyl Radical; Oxidation-Reduction; Picrates

Ethyl acetohydroxamate was efficiently arylated with diaryliodonium salts at room temperature under transition-metal-free conditions. The obtained O-arylated products were reacted in situ with ketones under acidic conditions to yield substituted benzo[b]furans through oxime formation, [3,3]-rearrangement, and cyclization in a fast and operationally simple one-pot fashion without using excess reagents. Alternatively, the O-arylated products could be isolated or transformed in situ to aryloxyamines or O-arylaldoximes. The methodology was applied to the synthesis of Stemofuran A and the formal syntheses of Coumestan, Eupomatenoid 6, and (+)-machaeriol B.

Topics: Benzofurans; Benzopyrans; Combinatorial Chemistry Techniques; Coumarins; Cyclization; Oximes; Phenols

Pd-catalytic C-S activation was successfully applied to initiate the cross-coupling of (2-methylthio-3-ester)benzofurans with 2-hydroxyphenylboronic acids and sequential intramolecular transesterification process under Liebeskind-Srogl conditions. Thus, a novel [3 + 3] annulation strategy for efficient synthesis of coumestan derivatives has been developed from readily available starting materials.

Topics: Benzofurans; Boronic Acids; Catalysis; Coumarins; Cyclization; Molecular Structure; Organometallic Compounds; Palladium

AMP-activated protein kinase (AMPK) has been proposed as a therapeutic target for the treatment of metabolic syndrome including obesity and type-2 diabetes. The bioassay-guided fractionation of an EtOAc-soluble extract of the stem bark of Erythrina abyssinica led to the isolation of a new coumestan, erythribyssin N (1), and two new benzofurans, erythribyssin F (2) and erythribyssin H (3), along with five known compounds (4-8). When tested for their stimulatory effects on AMPK activity at a concentration of 10 muM, compounds 4 and 5 showed potent activation, while compounds 1, 2, and 7 had moderate effects. These results suggest that benzofurans and coumestans may be new lead compounds for regulating the AMPK enzyme.

Topics: AMP-Activated Protein Kinases; Benzofurans; Coumarins; Erythrina; Molecular Structure; Plant Bark; Uganda

Two 2-phenylbenzofurans, lespedezavirgatol (1) and lespedezavirgatal (2), and a coumestan, lespedezacoumestan (3), were isolated from the aerial parts of Lespedeza virgata, together with nine known flavonoids. Their structures were determined on the basis of spectroscopic data. The three new compounds showed strong oxygen radical absorbance capacity and potent inhibition toward lipid peroxidation in both plasma and kidney homogenate of renal failure rats.

Topics: Animals; Antioxidants; Ascorbic Acid; Benzofurans; Coumarins; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Flavonoids; Kidney; Lespedeza; Lipid Peroxidation; Plants, Medicinal; Rats