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Chalcones As Promising Antitumor Agents by Targeting the P53 Pathway: an Overview and New Insights in Drug-Likeness

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Chalcones As Promising Antitumor Agents by Targeting the P53 Pathway: an Overview and New Insights in Drug-Likeness molecules Review Chalcones as Promising Antitumor Agents by Targeting the p53 Pathway: An Overview and New Insights in Drug-Likeness Joana Moreira 1,2,† , Joana Almeida 3,† , Lucília Saraiva 3,* , Honorina Cidade 1,2,* and Madalena Pinto 1,2,* 1 Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; [email protected] 2 Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Edifício do Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos s/n, 4450-208 Matosinhos, Portugal 3 LAQV/REQUIMTE, Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; [email protected] * Correspondence: [email protected] (L.S.); [email protected] (H.C.); [email protected] (M.P.); Tel.: +351-22-042-8584 (L.S.); +351-22-042-8688 (H.C.); +351-22-042-8692 (M.P.) † Authors contributed equally to this work. Abstract: The p53 protein is one of the most important tumor suppressors that are frequently inacti- vated 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 concern- ing 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 Citation: Moreira, J.; Almeida, J.; of MDM2. In this work, a literature review of natural and synthetic chalcones and their analogues Saraiva, L.; Cidade, H.; Pinto, M. Chalcones as Promising Antitumor potentially interfering with p53 pathway is presented. Moreover, in silico studies of drug-likeness of Agents by Targeting the p53 Pathway: chalcones recognized as p53–MDM2 interaction inhibitors were accomplished considering molecular An Overview and New Insights in descriptors, biophysiochemical properties, and pharmacokinetic parameters in comparison with Drug-Likeness. Molecules 2021, 26, those from p53–MDM2 in clinical trials. With this review, we expect to guide the design of new and 3737. https://doi.org/10.3390/ more effective chalcones targeting the p53 pathway. molecules26123737 Keywords: chalcones; antitumor activity; p53; MDM2; drug-likeness; pharmacokinetic properties Academic Editor: Federica Belluti Received: 28 April 2021 Accepted: 17 June 2021 1. Introduction Published: 19 June 2021 Chalcones are natural products possessing the common chemical scaffold of a 1,3- diphenyl-2-propen-1-one (Figure1). These natural products are widely occurring in plants Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in as precursors of other classes of flavonoids, being obtained by a mixed biosynthetic path- published maps and institutional affil- way via acetate-malonate and shikimate pathways [1]. Natural chalcones have attracted iations. a large amount of attention from the scientific community due to their broad and inter- Molecules 2021, 26, 3737 2 of 24 esting biological activities, including anticancer, cancer-preventative, anti-inflammatory, antidiabetic, antioxidant, antimicrobial, and neuroprotective activities, among others [2–9]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). FigureFigure 1. Structure of of chalcone. chalcone. The antitumor activity of chalcones seems to be mediated by a diverse set of cellular and molecular mechanisms, including the interference with the p53 pathway. The p53 Molecules 2021, 26, 3737. https://doi.org/10.3390/molecules26123737protein is one of the most important tumor suppressors.https://www.mdpi.com/journal/molecules As a transcription factor, p53 regulates the expression of many pro-apoptotic genes, as well of genes involved in cell cycle arrest, senescence, and DNA repair. In normal cells, which are not under stress conditions, the p53 protein seems to be rather unstable, having a short half-time. As a result, p53 is kept at very low levels and in the inactive state [10]. When cells start to experience stress conditions, p53 becomes active and stable in response to the multiple intra- and extracellular stress signals. When p53 accumulates in the nucleus, it can lead to apoptosis, cell-cycle arrest, and DNA repair [11]. Whether cells are under physiological or stress conditions, the activity and level of p53 are under tight control by diverse mechanisms, including by endogenous negative regulators. Murine double minute (MDM)2 is an E3 ubiquitin-protein ligase and the main endogenous negative regulator of p53 [12]. In normal cells, MDM2 maintains p53 at base levels by regulating its ubiquitination and degradation by the 26S proteasome. When the cell is exposed to stress, MDM2 significantly loses the binding affinity to p53, which results in p53 stabilization [13]. MDM2 is also a transcriptional target of p53, regulating its levels and activity with the creation of a feedback loop, which also regulates its own expression [14]. In addition to its ubiquitination property and proteasomal degradation, MDM2 inhibits the transcription activity of p53 (Figure 2) [15]. In addition to MDM2, MDMX is also implicated in the regulation of p53 activity, as it also inhibits p53 transcriptional function. Nevertheless, MDMX does not exhibit E3 ligase activity and does not directly promote degradation of p53, but it interacts with MDM2, affecting p53 and MDM2 expression levels [16]. Figure 2. Effects of MDM2 and MDMX in p53. p53 regulates MDM2 and MDMX transcription levels (red arrows), while MDM2 and MDMX inhibit p53 transcriptional function. MDM2 can also promote p53 nuclear export to the cytoplasm and its ubiquitin-mediated degradation by the proteasomes. MDM2 can also promote the nuclear degradation of p53 (polyubiquitination), MDMX ubiquitination, and its own ubiquitination and degradation. Ub: ubiquitin. Molecules 2021, 26, 3737 2 of 24 Figure 1. Structure of chalcone. Molecules 2021, 26, 3737 2 of 24 The antitumor activity of chalcones seems to be mediated by a diverse set of cellular and molecular mechanisms, including the interference with the p53 pathway. The p53 proteinThe is antitumor one of the activity most ofimportant chalcones tumor seems suppressors. to be mediated As bya transcription a diverse set offactor, cellular p53 andregulates molecular the expression mechanisms, of many including pro-apoptotic the interference genes, withas well the of p53 genes pathway. involved The in p53 cell proteincycle arrest, is one senescence, of the most and important DNA repair. tumor In suppressors. normal cells, As which a transcription are not under factor, stress p53 regulatesconditions, the the expression p53 protein of many seems pro-apoptotic to be rather genes, unstable, as well having of genes a short involved half-time. in cell cycle As a arrest,result,senescence, p53 is kept and at very DNA low repair. levels In normaland in cells,the inactive which are state not [10]. under When stress cells conditions, start to theexperience p53 protein stress seems conditions, to be rather p53 becomes unstable, active having and a stable short half-time.in response As to a the result, multiple p53 isintra- kept and at very extracellular low levels stress and signals. in the inactiveWhen p53 state accumulates [10]. When in the cells nucleus, start to it experience can lead to stressapoptosis, conditions, cell-cycle p53 arrest, becomes and DNA active repair and stable [11]. Whether in response cells to are the under multiple physiological intra- and or extracellularstress conditions, stress signals.the activity When and p53 accumulateslevel of p53 in are the under nucleus, tight it can control lead to by apoptosis, diverse cell-cyclemechanisms, arrest, including and DNA by endogenous repair [11]. negative Whether regulators. cells are under physiological or stress conditions,Murine the double activity minute and level (MDM)2 of p53 is are an under E3 ubiquitin-protein tight control by diverseligase and mechanisms, the main includingendogenous by endogenousnegative regulator negative of regulators.p53 [12]. In normal cells, MDM2 maintains p53 at base levelsMurine by regulating double minute its ubiquitination (MDM)2 is anand E3 degradation ubiquitin-protein by the ligase 26S proteasome. and the main When endoge- the nouscell is negative exposed regulator to stress, of MDM2 p53 [12 ].significantly In normal cells, loses MDM2 the binding maintains affinity p53 to at basep53, levelswhich byresults regulating in p53 its stabilization ubiquitination [13]. and MDM2 degradation is also a bytranscriptional the 26S proteasome. target of When p53, regulating the cell is exposedits levels to and stress, activity MDM2 with significantly the creation loses of a thefeedback binding loop, affinity which to also p53, regulates which results its own in p53expression stabilization [14]. [In13 ].addition MDM2 to is alsoits ubiquiti
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