456
Antitumor Steroids
4.3
Electrophilic 11
β
Derivative
Estrogenic and antiestrogenic activity of a
few 11
β
-ethyl, butyl, and decyl derivatives
of
E
2
bearing
various
electrophilic
functionalities
(i.e.
bromide,
bromo-
acetamido, (methylsulfonyl)oxy, and (
p
-
tolylsulfonyl)oxy) were determined with
MVLN
cells
(ER-dependent
luciferase
expression).
Ethyl
derivatives
were
mainly
estrogenic,
whereas
butyl
and
decyl
essentially
antiestrogenic
(most
compounds share a signiFcant binding
afFnity for ER).
Long-term treatment of MVLN cells with
OH-Tam progressively abolishes the abil-
ity of cells to express luciferase in response
to estrogens. This irreversible effect seems
to result from an epigenetic mechanism,
such as methylation or chromatin remod-
eling rather than gene mutation. It pro-
gressively affects the whole-cell population
and occurs by a Frst-order process, with
HO
TsO-(CH
2
)
10
OH
HO
OH
HN
Cl
O
HO
OH
N
Cl
O
HO
OH
O
I
HO
OH
O
N
Br
O
HO
OH
O
H
N
Br
O
HO
OH
O
N
Br
O
HO
OH
O
N
Cl
O
Fig. 11
Electrophilic derivatives of E
2
described in Sect. 4.3.
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