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Open AccessArticle

Synthesis, Biological Evaluation, and In Silico Studies of Novel Aminated Xanthones as Potential p53-Activating Agents

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
2
UCIBIO/REQUIMTE, Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
3
CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Novo Edificio do Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, Portugal
*
Authors to whom correspondence should be addressed.
Academic Editor: Qiao-Hong Chen
Molecules 2019, 24(10), 1975; https://doi.org/10.3390/molecules24101975
Received: 7 May 2019 / Revised: 20 May 2019 / Accepted: 21 May 2019 / Published: 22 May 2019
(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)
Xanthone scaffold has been regarded as an attractive chemical tool in the search for bioactive molecules with antitumor activity, and in particular two xanthone derivatives, 12-hydroxy-2,2-dimethyl-3,4-dihydro-2H,6H-pyrano [3,2-b]xanthen-6-one (4) and 3,4-dimethoxy-9-oxo-9H-xanthene-1-carbaldehyde (5), were described as a murine double minute 2 (MDM2)-p53 inhibitor and a TAp73 activator, respectively. The xanthone 5 was used as a starting point for the construction of a library of 3,4-dioxygenated xanthones bearing chemical moieties of described MDM2-p53 inhibitors. Eleven aminated xanthones were successfully synthesized and initially screened for their ability to disrupt the MDM2-p53 interaction using a yeast cell-based assay. With this approach, xanthone 37 was identified as a putative p53-activating agent through inhibition of interaction with MDM2. Xanthone 37 inhibited the growth of human colon adenocarcinoma HCT116 cell lines in a p53-dependent manner. The growth inhibitory effect of xanthone 37 was associated with the induction of G1-phase cell cycle arrest and increased protein expression levels of p53 transcriptional targets. These results demonstrated the potential usefulness of coupling amine-containing structural motifs of known MDM2-p53 disruptors into a 3,4-dioxygenated xanthone scaffold in the design of novel and potent p53 activators with antitumor activity and favorable drug-like properties. Moreover, in silico docking studies were performed in order to predict the binding poses and residues involved in the potential MDM2-p53 interaction. View Full-Text
Keywords: antitumor activity; computational docking; MDM2-p53 interaction; xanthones; yeast-based assays antitumor activity; computational docking; MDM2-p53 interaction; xanthones; yeast-based assays
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MDPI and ACS Style

Lemos, A.; Gomes, A.S.; Loureiro, J.B.; Brandão, P.; Palmeira, A.; Pinto, M.M.M.; Saraiva, L.; Sousa, M.E. Synthesis, Biological Evaluation, and In Silico Studies of Novel Aminated Xanthones as Potential p53-Activating Agents. Molecules 2019, 24, 1975. https://doi.org/10.3390/molecules24101975

AMA Style

Lemos A, Gomes AS, Loureiro JB, Brandão P, Palmeira A, Pinto MMM, Saraiva L, Sousa ME. Synthesis, Biological Evaluation, and In Silico Studies of Novel Aminated Xanthones as Potential p53-Activating Agents. Molecules. 2019; 24(10):1975. https://doi.org/10.3390/molecules24101975

Chicago/Turabian Style

Lemos, Agostinho; Gomes, Ana S.; Loureiro, Joana B.; Brandão, Pedro; Palmeira, Andreia; Pinto, Madalena M.M.; Saraiva, Lucília; Sousa, Maria E. 2019. "Synthesis, Biological Evaluation, and In Silico Studies of Novel Aminated Xanthones as Potential p53-Activating Agents" Molecules 24, no. 10: 1975. https://doi.org/10.3390/molecules24101975

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