Synthesis of Aminated Xanthones: Exploiting Chemical Routes to Reach for Bioactive Compounds

Typically, about 90% of drug candidates are N-containing, and an even higher amount are O-containing. As a consequence, it is not surprising that alkylation and arylation of groups with nitrogen and oxygen emerge as major reactions to obtain bioactive compounds.¹ Xanthones are a class of O-heterocycles characterized by a dibenzo-γ-pyrone nucleus. This scaffold may be considered a “privileged structure” able of providing useful ligands for several types of receptors and/or enzymes targets by judicious structural modifications.² In our search for potential anticancer drugs we pursuit with a hybridization approach of N-containing xanthones. N-Substitution is typically achieved by one of the following strategies: (i) direct reaction with alkyl-X or aryl-X, (ii) reductive alkylation using an appropriate aldehyde.

Herein, exploiting chemical routes to reach for bioactive N-containing xanthones with will be shared. The synthesis of new xanthone derivatives proceeds by both strategies and the respective strengths and weakness will be presented in a “medchem” perspective. Although chemical route (i) (S_N2 reactions and nucleophilic aromatic substitutions) provided interesting antitumor derivatives,³ the reductive amination (ii) furnished a library of potential p53:MDM2 inhibitors with noticeable advantages such as: high-yield reactions, one-pot conversions, aliphatic amines with low potential to form reactive metabolites.

The use of a variety of (thio)xanthone building blocks, with various substituents, and different reaction conditions allowed us to develop a repertoire of N-transformations, often referred as the “chemist toolbox”.⁴ 

References

1. Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 2337–2347.
2. Pinto, M. M. M.; Sousa, M. E.; Nascimento, M. S. J. Curr. Med. Chem. 2005, 12, 2517-2538.
3. Palmeira, A.; Vasconcelos, M. H.; Paiva, A.; Fernandes, M. X.; Pinto, M.; Sousa. E. Biochem. Pharmacol. 2012, 83, 57–68.
4. Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451-3479.

 Acknowledgments: This research was partially supported by ERDF through the COMPETE and national funds through FCT, under the project PEst-C/MAR/LA0015/2013.