IJUP08 - Universidade do Porto

Prenylated and bromoalkylated xanthones as potential antitumor
agents: synthesis and biological activities
A. Paiva 1,3 , E. Sousa 1,3 , M. Pinto 1,3 , A. Camões 2,3 , N. Nazareth 2,3 and M. S. J.
Nascimento 2,3
1 Department of Organic Chemistry, Faculty of Pharmacy, University of Porto, Portugal.
2 Department of Microbiology, 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.
In order to improve the growth inhibitory effect of 3,4-dihydroxyxanthone (1) on human
tumor cell lines [1], the synthesis of new prenylated and bromoalkylated derivatives was
planned. Three prenylxanthones (2-4), as well as two bromohexyloxyxanthones, (5, 6)
were obtained by different synthetic pathways (Fig. 1). The structures of compounds 2-6
were established by spectroscopic methods (IR, NMR of 1 H and 13 C, HMBC and HSQC)
and mass spectrometry.
O
O
1
OH
BrCH 2 CHC(CH 3 ) 2
K 2CO 3 ,DMF,reflux
OH
Br CH 2 CHC(CH 3 ) 2
K 2 CO 3 ,DMF,r.t.
Br(CH 2) 6Br
(drop-to-drop)
K 2 CO 3 ,DMF,r.t.
O
O
O
2
OH
O
+
O O
O
3
O
4
Fig. (1). Synthesis of prenylated and bromoalkylated xanthones.
5
O
O
O
O
The effects of xanthones 2-6 on the in vitro growth of estrogen receptor positive (ER +)
MCF-7 and estrogen receptor negative (ER −) MDA-MB-231 cells were investigated.
Prenylated compounds 2-4 and monobromoalkylxanthone 6 were more potent than the
parent compound 1. Moreover, compounds 2-4 revealed selectivity against ER(+) MCF-7
cells. Compound 2, the most potent derivative (GI50 = 5 µM, MCF-7), showed an
antiproliferative effect either on complete and steroid-free RPMI medium suggesting not to
be dependent on estrogenic stimulation. The growth inhibitory action of the antiestrogen 4hydroxytamoxifen
in ER(+) MCF-7 cell line was strongly enhanced by compound 2. This
is the first report of interactions between xanthones and an antiestrogen.
References:
[1] 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.
Br
O
Br
OH
+
O
O
O
6
OH
O
Br
66