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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
Based on the principles of rational drug design, a novel series of chalcone molecules were rationally designed by linking the resorcinol and the trimethoxyphenyl ring. The prop-2-ene-1-one molecule (Figure 5.6E), designed through SBDD way expressed inhibition of Hsp90 which results in complete suppression of several oncogenic molecules such as EGFR, Her2, Met, and Akt proteins, prevents H1975 cell proliferation (GI50 of 48 μM), and overcoming gefitinib-resistance. The molecular docking expressed a noteworthy interaction with Hsp90 target along with several interesting results which clearly supported the disruption of Hsp90 chaperone machinery. The resorcinol ring binds with the hydrophilic portion whereas the trimethoxyphenyl ring dominates in the hydrophobic part (–7.91 kcal/mol) while interacting with the Thr184, Asp93, Leu48, and Val186 residues through hydrogen-bonding and Van der Waals contact [46].
Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Chalcone (Figure 12.10) is an aromatic ketone and an enone that forms the central core within a variety of polyphenolic plant-based natural products known collectively as chalcones or chalconoids. Chalcones are related to the flavonoids in that the structure of their central core is similar to the flavone core (Figure 12.7) but with the B-ring broken open. Therefore, there is an assumption that chalcones may interact with the same pharmacological receptors as flavonoids provided they can take up a similar three-dimensional shape. Chalcones have a widespread distribution in fruits, vegetables, and teas. One of the best-known examples is xanthohumol (Figure 12.10), which is described in further detail below. Chemical structures of the parent chalcone core, and xanthohumol.
Role of Natural Agents in the Management of Diabetes
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Monika Elżbieta Jach, Anna Serefko
In a preclinical study with normal mice, seven bioactives isolated from rhizomes revealed a significant blood glucose-reduction effect, especially 2′,4′-dimethoxy-4-hydroxychalcone, liquiritigenin-7,4′-dibenzoate, and isoliquiritigenin (50, 50 and 200 mg/kg body weight, respectively). The structure-activity relationship signified that the ether and ester groups contained in these bioactive compounds are essential for the antidiabetic activity. The antidiabetic activity of chalcone derivatives is mediated by stimulation of PPARγ, and these flavonoids modify the activity of intracellular enzymes e.g., glucosidases (Gaur et al., 2014). The licorice extract inhibits α-glucosidase and α-amylase enzyme activity, leading to diminution of disaccharide hydrolysis (Karthikeson and Lakshmi, 2017).
Research progress of natural products and their derivatives against Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Jin-Ying Liu, Hong-Yan Guo, Zhe-Shan Quan, Qing-Kun Shen, Hong Cui, Xiaoting Li
Chalcone, also known as diphenylpropenone, is a flavonoid composed of phenolic compounds, one of the largest groups of bioactive natural products. Its unique chemical structural features have inspired the synthesis of numerous chalcone derivatives. To explore their ability to reduce intracellular amyloid and associated oxidative damage, more than ten natural products, including chalcone, were assayed, and trans-chalcone and baicalein were found to be the most potent compounds46. All compounds were flavonoids. Six natural chalcones were assayed, and most compounds exhibited inhibitory effects against both MAO-B and AChE47. Chalcone has a lower molecular weight, structural modification on its skeleton can increase the interaction with the target. Chalcone is more suitable for multi-target drug molecular design. This can greatly improve biological activity (Figure 6).
Effects of Dietary Phytochemicals on DNA Damage in Cancer Cells
Published in Nutrition and Cancer, 2023
Yang Ye, Ying Ma, Mei Kong, Zhihua Wang, Kang Sun, Fang Li
Chalcone compounds and their derivatives are found in safflower, licorice, and many other plants. These compounds are simple scaffolds for many naturally occurring compounds; their biological activities are diverse, and they are easy to synthesize (122). Studies have shown that a chalcone derivative significantly increases ROS levels in melanoma cells, activates the ATM/ATR signaling pathway, and enhances the expression of the DNA damage marker γH2AX, thus promoting apoptosis (35). Helmy et al. (123) used the Claisen–Schmidt condensation reaction to produce the targeted chalcone derivatives 7a–I. The extent of DNA fragmentation and damage in lung and liver cancer cells increased significantly after treatment with the derivatives compared with those of the control group. Another chalcone derivative (2-hydroxy-3′,5,5′-trimethoxychalcone) activates DDR by inducing increased levels of the tumor suppressor protein p53 and phosphorylating histone H2AX on Ser139 while increasing ROS levels (36). Therefore, developing chalcone and/or chalcone derivates as novel anticancer drugs is a promising strategy.
Activation of Nrf2 signaling pathway by natural and synthetic chalcones: a therapeutic road map for oxidative stress
Published in Expert Review of Clinical Pharmacology, 2021
Melford Chuka Egbujor, Sarmistha Saha, Brigitta Buttari, Elisabetta Profumo, Luciano Saso
The toxicological scrutiny of the compounds is important to drive a decision for a novel chemical entity to be used as a therapeutic drug in practical applications [135]. So far, extensive research on efficacy, safety, and pharmacokinetic profile of natural and synthetic chalcones have been reported [136]. Physicochemical potency toxicity profiles showed that chalcones followed the Lipinski rule of five (requisite parameters for druggability) with 91.91% oral absorption values [137]. Furthermore, the maximum recommended daily dose of chalcone was determined by the local weighed approach, which showed that chalcone has a high tolerated daily dose with a score of 0.489 log mg/kg/day [137]. Toxicity profiling further confirmed an LD50 value of 2.346 log mg/kg and the oral rat chronic toxicity score of 1.403 log mg/kg per day with no skin sensations [137]. Some other reports based on the criteria of OECD also confirmed no mortality, no severe toxic effects and noncarcinogenic nature, even at the highest dose of 2000 mg/kg [138]. These results suggested safe efficacy associated with administration of chalcone.