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

Abstract

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.

From Natural Products to New Synthetic Small Molecules: A Journey through the World of Xanthones

“…Another example of hybridization approach was also explored by us regarding the potential of aminated xanthones to disrupt the MDM2-p53 interaction using an yeast cell-based assay [ 101 ]. Previous studies developed by our group disclosed two xanthone derivatives, pyranoxanthone 22 ( Figure 7 ) and 1-carbaldehyde-3,4-dimethoxyxanthone 7 ( Figure 4 ) as MDM2-p53/TAp73 inhibitors.…”

Synthesis of a Small Library of Nature-Inspired Xanthones and Study of Their Antimicrobial Activity

“…The low yields obtained in this reaction are due to failure of the reaction to go to completion and other complications in the purification step. On the other hand, Wohl-Ziegler bromination of 1 and 2 using N-bromosuccinimide (NBS) brominating agent and benzoyl peroxide (BPO) as the radical initiator afforded 1-(dibromomethyl)-3,4-dimethoxy-9Hxanthen-9-one (7) [22] and 1-(dibromomethyl)-3,4,6-trimethoxy-9H-xanthen-9-one (8), respectively. Subsequent solvolytic displacement of bromine atoms of the gem-dibromomethylated derivatives 7 and 8 was successfully accomplished using 1-butyl-3-methylimidazolium tetrafluoroborate ((bmIm)BF 4 ) and water, under conventional heating, and furnished carbaldehydic xanthones 9 [22] and 10 in good yields.…”

Xanthones and Cancer: from Natural Sources to Mechanisms of Action

“…Recently, Lemos et al . synthesized a series of aminated xanthones with 3,4‐dioxigenated chemical moieties containing MDM2‐p53 inhibitors.…”

“…Recently, Lemos et al [157] synthesized a series of aminated xanthones with 3,4-dioxigenated chemical moieties containing MDM2-p53 inhibitors. Some xanthones inhibited the growth of human colon adenocarcinoma HCT116 cell lines in a p53-dependent manner.…”