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Heat Shock Protein 90 (Hsp90) Inhibitory Potentials of Some Chalcone Compounds as Novel Anti-Proliferative Candidates
Published in P. Mereena Luke, K. R. Dhanya, Didier Rouxel, Nandakumar Kalarikkal, Sabu Thomas, Advanced Studies in Experimental and Clinical Medicine, 2021
Debarshi Kar Mahapatra, Sayan Dutta Gupta, Sanjay Kumar Bharti, Tomy Muringayil Joseph, Józef T. Haponiuk, Sabu Thomas
Flavokawain B (Figure 5.6H) has also been reported to demonstrate anti-proliferative activity against human oral carcinoma HSC-3 cells and hepatotoxicity against HepG2 cells by inducing cell-cycle arrest, transcriptional responses, and apoptosis through disruption of Hsp90 chaperone machinery [51, 52].
Herbs with Antidepressant Effects
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
It has been reported that some individuals using kava have suffered severe and even fatal hepatotoxicity. In a 2003 paper, this relationship was somewhat softened. It was noted that out of 19 cases in Germany, only one was unequivocally related to kava. Nonetheless, it was prudently suggested that patients using kava be monitored.14 Subsequent analysis of the problem has provided little resolution. Indeed, it even became suspected that mold toxins similar to aflatoxin may have contaminated kava herb stored in hot humid conditions in the tropical Pacific.15 However, studies over the last decade have shown that kava contains a toxic component, identified to be flavokawain B, that kills liver cells. Interestingly, exogenous glutathione rescues hepatocytes from flavokavain B-induced death.16
Application of the Mannich reaction in the structural modification of natural products
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Miao-Xia Pu, Hong-Yan Guo, Zhe-Shan Quan, Xiaoting Li, Qing-Kun Shen
Flavokawain B, a 20-hydroxy-4, 6-dimethoxy chalcone isolated from the roots of kava, showed remarkable anti-proliferative activity against different cancer cell lines. However, the content of flavokawain B in plants is low; therefore, Liu et al.50 first synthesised the lead compound flavokawain B through Houben-Hoesch acetylization, regioselective O-methylation, and Claisen–Schmidt condensation with benzaldehyde, and seven flavokawain B Mannich base derivatives were synthesised through the Mannich reaction. Their inhibitory activity on AChE was evaluated (Table 2). Pharmacological data showed that four compounds displayed potent activities against AChE with IC50 values <20 µM. Among them, the inhibitory activity of AChE of compound 37 (Figure 3) was the strongest (IC50 = 4.15 µM), at twice that of the positive control drug rivastigmine (IC50 = 10.54 µM). The log p values of compound 37 was 1.75, indicating that it was sufficiently lipophilic to cross the blood-brain barrier in vivo.
Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Moran Sun, Minghua Yuan, Yingying Kang, Jinling Qin, Yixin Zhang, Yongtao Duan, Longfei Wang, Yongfang Yao
CA-4 has provided a structural model for the design of new analogs with anti-vascular and anticancer profiles. Chalcones, bearing an α, β-unsaturated carbonyl moiety, can be viewed simplistically as keto-stilbenes and mimics a portion of CA-410. Accordingly, chalcones have been used as a source of microtubule-destabilizing agents binding at the colchicine-site with the purpose to improve the chemical stability of CA-4. Flavokawain A was a promising apoptosis inducer and arrested cell cycle at G2/M against HER2-overexpressing breast cancer cells (Figure 1)10. Incorporated the aryl substitution pattern of CA-4 into chalcones afford compound 1a, which displayed low cytotoxicity towards normal cells and greater metabolic stability than CA-4, along with potent antiproliferative activity against drug resistant cells11. Chalcone 1b (TUB091) exhibit vascular disrupting effects and anti-metastatic activity similar to that of CA-4P12.
2′,4-Dihydroxy-3′,4′,6′-trimethoxychalcone from Chromolaena odorata possesses anti-inflammatory effects via inhibition of NF-κB and p38 MAPK in lipopolysaccharide-activated RAW 264.7 macrophages
Published in Immunopharmacology and Immunotoxicology, 2018
Rana Dhar, Rungruedee Kimseng, Ratchanaporn Chokchaisiri, Poonsit Hiransai, Tanyarath Utaipan, Apichart Suksamrarn, Warangkana Chunglok
NF-κB is a transcription factor that plays a pivotal role in regulating transcription of proinflammatory genes. NF-κB consists of a p50 and p65 subunits, which bind with its inhibitor IκB. Phosphorylation of IκB by IKK leads to translocation of cytoplasmic p65 to nucleus, thereby activating transcription of the target genes8. We have demonstrated that the chalcone 1 inhibited phosphorylation of IκB molecules thereby hampering NF-κB activation. In line with our findings, a chalcone named flavokawain B has been shown to decrease NF-κB activation by degrading the inhibitory subunit IκBα as well as inhibiting the activation of IKK36. Butein, a tetrahydroxychalcone, inhibits NF-κB via direct inhibition of IKK at cysteine-179, which is an essential cysteine residue for IKK activity37. Thus, it is suggested that the main inhibitory mechanism of these compounds may be due to inactivation of the NF-κB24. Besides the involvement of the NF-κB signaling pathway, the chalcone specifically inactivated p38 MAPK in LPS-stimulated RAW 264.7 cells. Accumulating evidence suggests that p38 MAPK plays a significant role in macrophage-mediated inflammation38. p38 MAPK regulates expression of proinflammatory mediators, such as TNF-α, IL-6, and NO, via subsequent activation of transcription factor AP-1 (c-Jun and c-Fos)39. It is suggested that p38 MAPK activation suppressed by chalcone may be related to an effect on a heme oxygenase-dependent pathway40, and this will be further investigated.