- COMPOSITIONS AND METHODS OF TREATING UPS-ASSOCIATED DISEASES
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The present invention relates to methods for treating a disease characterized by aberrations in the ubiquitin/proteasome system (UPS).
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- Discovery of isoliquiritigenin analogues that reverse acute hepatitis by inhibiting macrophage polarization
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Screening a natural product library of 850 compounds yield isoliquiritigenin as an effective anti-inflammatory agent by inhibiting the production of pro-inflammatory NO induced by Pam3CSK4, while its activity accompanied by toxicity. Further studies obtained the optimized isoliquiritigenin derivative SMU-B14, which can inhibit Pam3CSK4 triggered toll-like receptor 2 (TLR2) signaling with low toxicity and high potency. Preliminary mechanism studies indicated that SMU-B14 worked through TLR2/MyD88, phosphorylation of IKKα/β, leading to the reduce degradation of NF-κB related IKBα and p65 complex, then inhibited the production of inflammatory cytokines, such as TNF-α, IL-6, IL-1β both in human and murine cell lines. Subsequent polarization experiments showed SMU-B14 significant reversed the polarization of M1 phenotype primary macrophage activated by Pam3CSK4 in vitro, and reduced the infiltration of neutrophil and polarization of M1-type macrophage, decreased serum alanine transaminase (ALT), as a result protected liver from being injured in vivo. In summary, we obtained an optimized lead compound SMU-B14 and found it functionally blocked TLR2/MyD88/NF-κB signaling pathway to down-regulate the production of inflammatory cytokines resulted significant liver protection property.
- Yang, Junjie,Hu, Fanjie,Guo, Chengjun,Liang, Yuqing,Song, Haiying,Cheng, Kui
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- Synthesis and antibacterial activity of chalcones bearing prenyl or geranyl groups from Angelica keiskei
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Chalcones bearing prenyl or geranyl groups from Angelica keiskei, such as 4-hydroxyderricin (1a), xanthoangelol (1e), xanthoangelol F (1f), xanthoangelol H (2), deoxyxanthoangelol H (3), and deoxydihydroxanthoangelol H (4) and their derivatives were synthesized. From the evaluation of antibacterial activity of the synthesized chalcones, 1a, isobavachalcone (1b), 1e, 1f, bavachalcone (5a), and broussochalcone B (5b) were found to inhibit Gram-positive bacteria.
- Sugamoto, Kazuhiro,Matsusita, Yoh-Ichi,Matsui, Kana,Kurogi, Chiaki,Matsui, Takanao
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p. 5346 - 5359
(2011/08/04)
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- THERAPEUTIC AGENT
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A therapeutic agent and prophylactic agent for a disease accompanying an abnormality in an amount of insulin or insulin response, an agent for an insulin-mimetic action, a food, beverage and feed, an agent for enhancing glucose uptake into a cell, and an agent for inducing differentiation into an adipocyte, characterized in that each comprises as an effective ingredient at least one compound selected from the group consisting of a chalcone compound, an acetophenone compound, a coumarin compound, a phthalide compound, derivatives thereof, and pharmacologically acceptable salts thereof.
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Page/Page column 58
(2010/11/08)
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- A new synthesis of flavonoids via Heck reaction
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Several naturally occuring flavonoids have been synthesised following a new proposed method based on the use of the Heck reaction. The key step involves the coupling of an aryl vinyl ketone with an aryl iodide. This procedure affords the flavonoid moiety in a single step.
- Bianco, Armandodoriano,Cavarischia, Claudia,Farina, Angela,Guiso, Marcella,Marra, Carolina
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p. 9107 - 9110
(2007/10/03)
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- Synthesis and aromatase inhibitory activity of flavanones
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Purpose. Aromatase inhibitors are known to prevent the conversion of androgens to estrogens and play a significant role in the treatment of estrogen dependent diseases such as breast cancer. Some flavonoids have been reported as potent aromatase inhibitors; therefore, in an effort to develop novel anti breast cancer agents, B ring substituted flavanones with a 7-methoxy group on A ring were synthesized and tested to assess their ability to inhibit aromatase activity and to determine the optimal B ring substitution pattern. Methods. A series of flavanones was prepared by cyclisation of 2′hydroxychalcones previously obtained by Claisen-Schmidt condensation and the aromatase inhibitory activity of these compounds was investigated using human placental microsomes and radiolabeled [1,2,6,7-3H]-androstenedione as substrate. Results. Almost all flavanones exhibited inhibitory effect on the aromatase activity but their potency was dependent on their B ring substitution pattern. Hydroxylation at position 3′ and/or 4′ enhanced the anti-aromatase activity; thus, 3′,4′-dihydroxy-7-methoxyflavanone was found to be twice more potent than aminoglutethimide, the first aromatase inhibitor clinically used. Conclusions. These results indicated that these flavanones could be considered as potential anti breast cancer agents through the inhibition of aromatase activity and allowed us to select some of these compounds as skeleton for the development of flavonoid structurally-related aromatase inhibitors.
- Pouget,Fagnere,Basly,Besson,Champavier,Habrioux,Chulia
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p. 286 - 291
(2007/10/03)
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- Synthesis of flavonoids and their effects on aldose reductase and sorbitol accumulation in streptozotocin-induced diabetic rat tissues
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Aldose reductase, the key enzyme of the polyol pathway, and oxidative stress are known to play important roles in the complications of diabetes. A drug with potent inhibition of aldose reductase and oxidative stress, therefore, would be a most promising drug for the prevention of diabetic complications. The purpose of this study was to develop new compounds with these dual-effects through synthesis of chalcone derivatives and by examining the structure-activity relationships on the inhibition of rat lens aldose reductase as well as on antioxidant effects. A series of 35 flavonoid derivatives were synthesized by Winget's condensation, oxidation, and reduction of appropriate acetophenones with appropriate benzaldehydes. The inhibitory activity of these derivatives on rat lens aldose reductase and their antioxidant effects, measured using Cu2+ chelation and radical scavenging activities on 1,1-diphenyl-picrylhydrazyl in-vitro, were evaluated. Their effect on sorbitol accumulation in the red blood cells, lenses and sciatic nerves of streptozotocin-induced diabetic rats was also estimated. Among the new flavonoid derivatives synthesized, those with the 2′,4′-dihydroxyl groups in the A ring such as 2,4,2′,4′-tetrahydroxychalcone (22), 2,2′,4′-trihydroxychalcone (11), 2′,4′-dihydroxy-2,4-dimethylchalcone (21) and 3,4,2′,4′-tetrahydroxychalcone (18) were found to possess the highest rat lens aldose reductase inhibitory activity in-vitro, their IC50 values (concentration of inhibitors giving 50 % inhibition of enzyme activity) being 1.6 × 10-7, 3.8 × 10-7, 4.0 × 10-7 and 4.6 × 10-7 M, respectively. All of the chalcones tested except 3, 18, 23 with o-dihydroxy or hydroquinone moiety showed a weak free radical scavenging activity. In the in-vivo experiments, however, compound 18 with o-dihydroxy moiety in the B ring showed the strongest inhibitory activity in the accumulation of sorbitol in the tissues. It also showed the strongest activity in transition metal chelation and free radical scavenging activity. Of the 35 4,2′-dihydroxyl and 2′,4′-dihydroxyl derivatives of flavonoid synthesized, including chalcone, flavone, flavanone, flavonol and dihydrochalcone, some chalcone derivatives synthesized were found to possess aldose reductase inhibition and antioxidant activities in-vitro as well as inhibition in the accumulation of sorbitol in the tissues in-vivo. 3,4,2′,4′-Tetrahydroxychalcone (18, butein) was the most promising compound for the prevention or treatment of diabetic complications.
- Lim, Soon Sung,Jung, Sang Hoon,Ji, Jun,Shin, Kuk Hyun,Keum, Sam Rok
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p. 653 - 668
(2007/10/03)
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- Synthesis and description of chalcone-like compounds, inhibitors of aldose reductase
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A series of hydroxy- and hydroxy-methoxychalcones was synthesized and the inhibitory activity and selectivity of the compounds towards bovine lens aldose reductase (AR) were tested. All the compounds display affinity for AR. The most active proved to be 1-(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl)propen-1-one (isoliquiritigenin, IC50= 7.60 μM). The selectivity of this compound was also tested, its inhibitory activity being assayed against glutathione reductase and sorbitol dehydrogenase.
- Severi,Costantino,Benvenuti,Vampa,Mucci
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p. 128 - 136
(2007/10/03)
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