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Synthesis of Aminated Xanthones: Exploiting Chemical Routes to Reach for Bioactive Compounds
Emília Sousa * 1, 2 , Agostinho Lemos 1 , Ana Sara Gomes 1, 3 , Sara Cravo 1 , Madalena Pinto 1, 2
1  Department of Chemical Sciences, Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Porto, Portugal
2  CIIMAR – Interdisciplinary Centre of Marine and Environmental Research, Portugal
3  Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Portugal

Published: 02 November 2015 by MDPI AG in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1
10.3390/ecmc-1-A022
Abstract:

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) (SN2 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.

 

Keywords: Ullmann Coupling, Reductive Amination, Xanthones, Antitumor agents
Comments on this paper
Hassan Bousbaa
Aminated Xanthones ...on the road of Bioactive compounds
Nice work!
Cheers
Hassan
Carla Fernandes
Very interesting research! Nice presentation!
Maria Emília Sousa
Dear Friends, thank you for your time in assisting this conference!



 
 
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