450
Antitumor Steroids
this remark also holds for nonsteroidal
cytotoxic derivatives (i.e. diphenyl and
triphenylethylene (anti)estrogens).
In the following years, accumulation of
data concerning the receptor’s structure,
binding requirement, and mode of action
(previous sections) dictated new guide-
lines for syntheses. Research axes of the
last decade are overviewed in the follow-
ing paragraphs.
4.1
Organometallic Estradiol Derivatives
The advance in organometallic chemistry
associated with the discovery of the antitu-
mor activity of cisplatin led to the analysis
of the potential use of metal-conjugated
estrogens. Since cisplatin is unsuitable for
breast cancer treatment, the search con-
centrates mainly on non-platinum metal
complexes such as cyclopentadienyl cy-
cles of Ru, Ti, Fe, Co, and so on, which
appear attractive in cancer chemother-
apy. Nonetheless, cisplatin was also linked
with the hope of extending its therapeu-
tic use. While DNA is the expected target
of such drugs, some of them were found
to irreversibly associate with the recep-
tor, a behavior that may produce unusual
biological properties.
Unfortunately, endocrine and therapeu-
tic activity of most of the metal-conjugated
estrogens has not yet been explored. Inves-
tigations mainly concern their binding to
the receptor. The effect of ER-positive and
ER-negative cell lines has been assessed in
only a few cases.
4.1.1
A-ring Complexion
An
important
feature
displayed
by
organometallic clusters is the possibility
of their complexion on either the
α
-or
β
-
side of the steroid A-ring (Fig. 6). Studies
conducted with chromium and ruthenium
complexes reveal that a
π
-organometallic
adduct
on
the
β
-face
prevents
the
binding of E
2
to the receptor while its
addition on the
α
-face maintains some
binding af±nity. Of these compounds,
the neutral chromium complex displayed
the
highest
binding
af±nity
(
30%
of
E
2
).
Although
the
cationic
species
Cp
Ru
+
failed
to
seriously
alter
the
binding of the hormone, as demonstrated
HO
OH
A
3
HO(CH
2
)
3
O
Cr(CO)
3
HO
Ru
+
HO
Rh
+
CF
3
SO
3
(CF
3
SO
3
)
2
Fig. 6
Organometallic E
2
derivatives – chemical formulas of A-ring
substituted derivatives described in Sect. 4.1.1. Binding afFnity for ER of the
organometallic abduct is higher on the
α
face of A-ring those on its
β
face.
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