IJUP08 - Universidade do Porto

Antitumor and antifungal activities of xanthonic derivatives,
potential inhibitors of steroid sulfatase
E. Costa 1,3 , E. Sousa 1,3 , N. Nazareth 2,3 , M. S. J. Nascimento 2,3 , L. Vale-Silva 2,3 , E.
Pinto 2,3 and M. Pinto 1,3
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.
The enzyme steroid sulfatase (STS) has received increasing attention as a drug target, due
to its role in the pathogenesis of several diseases, in particular estrogen-dependent tumors,
with STS inhibitors entering in preclinical phases [1].
This work includes the synthesis of rigid analogues of the potent inhibitor of STS,
BENZOMATE (1): xanthone-3,6-O,O-bis(sulfate) (7), 1-hydroxyxanthone-2-O-sulfate (8)
and xanthone-3,4-O,O-bis(sulfate) (9). Other two precursors/analogues were obtained, the
3,6-dihydroxyxanthone (2) and the 2,2’,4,4’-tetracethylbenzophenone (6). These five
derivatives (2, 6-9) as well as the raw material 5 were investigated for their antifungal
activity and capacity to inhibit the in vitro growth of human tumor cell lines.
O
H 2 NO 2 SO
O
1
O
OSO 2 NH 2
O
HO O
2
OH
O OH
O
O
3 4
HO OH AcO OAc -O SO O OSO -
3 3
OH OH
OAc OAc
O
O
5 6 7 8
9
O
The synthetic pathway from 2,2’,4,4’-tetrahydroxybenzophenone (5), through dry heating
in furnace (180ºC) afforded 3,6-dihydroxyxanthone (2) in a very good yield (85%).
Dihydroxyxanthones 2-4 were treated with sulfur trioxide-pyridine in dimethylacethamide
to furnish the xanthonic sulfate derivatives, 7, 8 and 9.
The effect of compounds 2-9 on the growth of MCF-7 (breast adenocarcinoma), NCI-H460
(non-small cell lung cancer) and SF-268 (CNS carcinoma) cell lines was evaluated. 3,6-
Dihydroxyxanthone (2), 2,2’,4,4’-tetrahydroxybenzophenone (5) and 2,2’,4,4’tetracethylbenzophenone
(6) were shown to be active on all tumor cell lines (GI50‹150
μM). Regarding antifungal activity investigation, compounds 2, 5 and 6 showed a slight
inhibitory effect against Microsporum gypseum and Trichophyton mentagrophytes at 125
μg/ml.
References:
[1] Nussbaumer P. and Billich A. (2004), Steroid Sulfatase Inhibitors, Medicinal Research
Reviews, 24, 529-576.
Acknowledgments: FCT (I&D, nº226/94), FEDER, POCI for financial support.
OH
-
O OSO H
3
OSO 3
-
O
O
OH
OSO 3
OH
OSO 3
-
-
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