IJUP08 - Universidade do Porto

Synthesis of xanthone derivates for in vitro and in vivo biological
activity studies
J. Siroka 1,2 , E. Sousa 2,3 and M. Pinto 2,3
1 Department of Organic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University in
Prague, Czech Republic.
2 Department of Organic Chemistry, Faculty of Pharmacy, University of Porto, Portugal.
3 Research Centre of Organic Chemistry, Phytochemistry and Pharmacology of the University of
Porto (CEQOFFUP), Faculty of Pharmacy, University of Porto, Portugal
Xanthone derivatives are heterocyclic compounds with the dibenzo-γ-pyrone as the main
molecular moiety. They contain different types of substituents in different positions,
leading to a large variety of pharmacological activities [1]. 3,4-Dihydroxyxanthone (1, Fig.
1) was revealed as a hit compound in a study involving the investigation of the inhibitory
effect of oxygenated xanthones on several human tumor cell lines [2].
In order to obtain enough quantity for in vivo assays an for further molecular
modifications, the synthesis of 3,4-dihydroxyxanthone (1) was accomplished (Fig. 1): the
condensation of 1,2,3-trimethoxyphenol (2) with the appropriate substituted benzoyl
chloride 3 afforded
OMe
OMe
OMe
2
+
O
O
1
O
O
6
3
OH
CHO
HCO
OH
Friedel-Crafts acylation
COCl
Et2O, AlCl3 OMe
OH
Duff Formylation
HMTA (hexamethylentetramin)
CF3COOH OH
r.t. 22h
MeOH, H 2 O, NaOH, reflux/47h
Demethylation
C6H5CH3 , AlCl3 , 70 ºC/13h
Fig. 1. Synthesis of compounds 1 and 2.
O
OMe
OMe OH
OMe
4
O
O
5
O
O
Base-catalized cyclization
OMe
OMe
CHO
OMe
OMe
benzophenone 4 which was
further cyclized to give 3,4dimethoxyxanthone
(5).
Compound 5 was demethylated
to furnish 3,4dihydroxyxanthone
(1).
Additionally, the synthesis of
reactive formylated derivatives
of xanthones, 1 and 5, was
attempted by Duff formylation.
Only 1-formyl-3,4dihydroxyxanthone
(6) was
obtained by this procedure.
Compound 6 will be used as a
building block on the
construction of a library of amine
xanthonic derivatives to
investigate antitumor activity.
References:
[1] Pinto, M., Sousa, E., Nascimento, M. S. J. (2005), Xanthone derivatives: new insights in
biological activities, Current Medicinal Chemistry, 12, 2517-2538.
[2] Pedro M., Cerqueira, F., Sousa, M.E., Nacimento, M.S.J. and Pinto, M. (2002), Xanthones as
inhibitors of growth of human cancer cell lines and their effects on the proliferation of human
lymphocytes in vitro, Bioorganic Medicinal Chemistry, 10 (12), 3725-3730.
Acknowledgments: FCT (I&D, nº226/94), FEDER, POCI for financial support.
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