Abstract
The p53 protein is one of the most important tumor suppressors that are frequently inactivated in cancer cells. This inactivation occurs either because the TP53 gene is mutated or deleted, or due to the p53 protein inhibition by endogenous negative regulators, particularly murine double minute (MDM)2. Therefore, the reestablishment of p53 activity has received great attention concerning the discovery of new cancer therapeutics. Chalcones are naturally occurring compounds widely described as potential antitumor agents through several mechanisms, including those involving the p53 pathway. The inhibitory effect of these compounds in the interaction between p53 and MDM2 has also been recognized, with this effect associated with binding to a subsite of the p53 binding cleft of MDM2. In this work, a literature review of natural and synthetic chalcones and their analogues potentially interfering with p53 pathway is presented. Moreover, in silico studies of drug-likeness of chalcones recognized as p53–MDM2 interaction inhibitors were accomplished considering molecular descriptors, biophysiochemical properties, and pharmacokinetic parameters in comparison with those from p53–MDM2 in clinical trials. With this review, we expect to guide the design of new and more effective chalcones targeting the p53 pathway.
Highlights
Chalcones are natural products possessing the common chemical scaffold of a 1,3diphenyl-2-propen-1-one (Figure 1)
Considering the importance of prediction of pharmacokinetic properties in the early stages of the drug discovery process to reduce the chance of failure during clinical trials, we predicted drug-likeness of chalcones reported as p53–MDM2 inhibitors considering molecular descriptors, biophysicochemical properties, and pharmacokinetic parameters in comparison with those of p53–MDM2 inhibitors in clinical trials
For prenylated chalcones, the presence in B ring of 4-bromo or 2,3-dimethoxy phenyl groups are favorable for the activity, while the presence of 2,3- or 3,5-dichloro phenyl groups was found to be associated with a decrease of the activity, with this reduction of effect observed for 4-fluoro prenylated chalcones The capacity of all compounds to inhibit the growth of HCT116 cells was evaluated, and prenylated chalcone 70, which was shown to be the most effective as inhibitor of the MDM2 effect on p53 in the yeast assay, was selected to further studies in human cancer cells [78]
Summary
Chalcones are natural products possessing the common chemical scaffold of a 1,3diphenyl-2-propen-1-one (Figure 1). To be mediated a diverse set of cellular regulates the expression of many pro-apoptotic genes, as well of genes involved in cell and molecular mechanisms, including the interference with the p53 pathway. E3 ubiquitin-protein ligase and the main conditions, activity and level of p53isare tight control by diverse mechanisms, endogenous negative regulator of regulators. MDM2 maintains p53 at base including by endogenous negative levels by regulating its ubiquitination and by theligase. P53 is frequently inactivated in cancer cells, either because the TP53 gene is mutated or deleted, or because the p53 protein is inhibited by endogenous negative regulators, MDM2. Some adverse effects have been demonstrated, namely, late because the TP53 gene is mutated or deleted, or because the p53 protein is inhibited by endogenous negative regulators, MDM2.
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