Bioorganic & Medicinal Chemistry Letters 12 (2002) 2093–2095
4,40-Benzophenone-O,O 0-disulfamate: A Potent Inhibitor
of Steroid Sulfatase
Peter Nussbaumer,* Melitta Bilban and Andreas Billich
NOVARTIS Research Institute, Brunnerstrasse 59, A-1235 Vienna, Austria
Received 26 March 2002; revised 14 May 2002; accepted 16 May 2002
Abstract—We investigated whether the benzophenone moiety can be used as core element of steroid sulfatase (STS) inhibitors.
While 4- and 3-benzophenone-O-sulfamates inhibit STS with IC50 values between 5 and 7 mM irrespective of additional hydroxy
and methoxy substituents at the second phenyl ring, benzophenone-O,O0-disulfamates show increased activity. With an IC50 value
of 190 nM the 4,40-derivative is the first small monocyclic STS inhibitor coming close to the potency of the steroidal standard
estrone sulfamate. # 2002 Elsevier Science Ltd. All rights reserved.
Steroid sulfatase (estrone sulfatase, E.C. 3.1.6.2., STS)
regulates the local production of estrogens from sys-
temic precursors, such as estrone sulfate and dehy-
droepiandrosterone sulfate in normal and malignant
breast tissues. There is increasing evidence that in breast
and endometrial tissues the steroid sulfatase pathway is
the major source of estrogens, which support the growth
of endocrine-dependent tumours. Inhibitors of STS are
therefore considered as potential new therapeutic agents
for the treatment of estrogen-dependent cancers.1
photophores, but its steric requirement limits wider
applicability.5
We asked whether for STS the benzophenone moiety
itself could be used as core element of a ligand and not
only as an appendix to known ligands. To estimate the
magnitude of the binding affinity of benzophenone-
based ligands we prepared the corresponding sulfamates
and tested them for their inhibitory potencies, analo-
gously to the successful search for a new STS substrate.6
Following this approach, we discovered benzophenone
disulfamates with high inhibitory potency against STS.
Both irreversible and reversible inhibitors of human
STS have been reported.2 All potent irreversible inhibi-
tors feature the sulfamate functionality, which is
responsible for the irreversible mode of action. While
with irreversible inhibitors blocking of enzyme activity
in the nanomolar range can be achieved, the few known
reversible inhibitors are less potent by several orders of
magnitude. The design of potent, reversible inhibitors is
hampered by the lack of the 3-D-structure of STS. In
contrast to the related arylsulfatases A and B,3,4 infor-
mation on structure and catalytic mechanism of STS is
not available. Photolabeling of the active site of an
enzyme is a way to get insight into the residues involved
in catalysis. We, therefore, envisaged the design and
synthesis of photolabeling ligands for STS. Incorpora-
tion of a benzophenone substituent in photolabeling
substrates has proven several advantages over other
Chemistry
The test compounds 1a–1l were synthesized by sulfa-
moylation of the corresponding hydroxybenzophenones
using sodium hydride followed by amidochlorosulfonic
acid7 (3-fold excess of both reagents) in dimethylforma-
mide. With 3,30- and 3,40-dihydroxybenzophenone as
starting material both, the mono- and the disulfamated
products were obtained (1g+1j and 1i+1k, respec-
tively). All test compounds were purified by silica gel
1
chromatography and characterized by H NMR, MS
(ESI), and, in the case of new compounds, also by
elemental analysis.
The non-commercially available phenolic precursors
were prepared as outlined in Scheme 1. Addition of in
situ generated methoxyphenyllithium salts 2 to TBDMS
protected hydroxybenzaldehydes 3 gave benzhydrol
*Corresponding author. Tel.: +43-1-86634-395; fax: +43-1-86634-
354; e-mail: peter.nussbaumer@pharma.novartis.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00381-5