Antitumor Steroids
457
a half-inactivation time of
10 days. 11
β
electrophile conjugates described here,
similarly suppresses the expression of
the luciferase gene; antiestrogenic elec-
trophiles were more potent than the estro-
genic ones but less efFcient than OH-Tam.
Of note, these antiestrogenic electrophiles
decrease cell proliferation with potency
less than OH-Tam.
These effects could not be ascribed to
an irreversible binding of the compounds
to ER since 11
β
-[(tosyloxy)decyl]E
2
(±ig.
11) solely shared such a property. A cys-
teine residue does not seem to be involved
in the covalent attachment of this com-
pound since it was not prevented by a
thiol-speciFc alkylating reagent (MMTS).
In fact, length and mobility of the
N
-decyl
side chain precluded the identiFcation of
the anchorage site. To overcome this draw-
back, 11
β
aryl analogs aimed to restrict
the localization of the electrophilic car-
bon to the
β
-side of the steroid were
synthesized (±ig. 11). Both cysteinyl (prob-
ably C381 and/or C530) and non-cysteinyl
residues located on the
β
-side and re-
mote from C11 of the steroid (distance
>
‘‘seven bonds’’) appear to be potential
electrophile covalent attachment sites for
such E
2
derivatives.
As for most other estrogens bearing
reactive groups, no data were reported
upon their potential use in antitumor
therapy.
See
also
Bioorganic
Chemistry;
Medicinal Chemistry.
Bibliography
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(1992)
Antitumor
Steroids
,
Academic Press, New York.
von Angerer, E. (1995) The estrogen receptor as
a target for rational drug design,
Molecular
Biology
Intelligence
Unit
,
Springer-Verlag,
Heidelberg, Germany.
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