Antitumor Steroids
451
by
α
-[Cp
Ru(17
β
-estradiol)][CF
3
SO
3
], an
increase in the positive charge of the
organic
moeity
(i.e.
Rh
++
)
appears
detrimental. This effect may be attributed
to an increase in acidity; the complexion
of
the
phenolic
A-ring
increases
its
acidity. In a basic medium, the complexed
phenolic
rings
are
transformed
into
the corresponding dienonylic rings with
the concomitant loss of 3-OH function
required
for
strong
association
with
the receptor.
4.1.2
7
α
and 11
β
Derivatives
Grafting
of
organometallic
clusters
in
these
strategic
regions
is
expected
to
be
relatively
well
tolerated
(Sect. 3.1).
Hence, various compounds have been
synthesized.
Nonradioactive Re systems are anal-
ogous to corresponding nonradioactive
systems containing
99m
Tc,
186
Re or
188
Re.
For this reason, they may be viewed as
prototypes for the production of drugs to
be used in imaging and radiotherapy. At-
tempts to produce 7
α
derivatives in which
the rhenium moeity is remote from E
2
by a long side chain led to the identi-
±
c
a
t
iono
faf
ewcompound
sw
i
thh
igh
binding af±nity (
15% of E
2
;F
ig
.7)
.The
polarity of these complexes was modi±ed
to improve biodistribution without loss of
binding af±nity by introducing (poly)ether
linkages into the 7
α
side chains. Attach-
ment of a rhenium complex in position
11
β
(Fig. 7) was also relatively well toler-
ated (binding af±nity
1
/
10 of E
2
). Tested
on a reported gene, this compound dis-
played an agonist activity almost as strong
as E
2
.
Linkage of a cobalt cluster in 11
β
(i.e.
11
β
-[(ethynyl) Co
2
(CO)
6
]estradiol; Fig. 7)
strongly
increases
the
stability
of
the
association
of
the
parent-free
ligand
with
the
receptor.
This
behavior
is
reminiscent of the high performance of
11
β
-chloromethylestradiol in ER binding
(almost irreversible binding in buffered
solution). Tested
in vitro
in MVLN cells
(MCF-7 cells stably transfected with an
estrogen responsive luciferase gene), this
cobalt conjugate displays a strong estro-
genicity (as effective as E
2
)
; no cytotoxicity
was recorded.
4.1.3
17
α
Derivatives
Various
organometallic
moeities
(rhe-
nium, cobalt, ruthenium, tungsten, etc.)
fail to strongly affect the binding af±n-
ity of E
2
fo
rERwhenl
inkedini
t
s17
α
position at the end of a rigid ethynyl spacer
(Fig. 8). In contrast, the af±nity largely
decreases when the spacer is shortened
to a simple sp
3
carbon atom con±rm-
ing that the ER-HBD possesses a subsite
able to accommodate rigid narrow sub-
stituents. Af±nity also decreases when the
organometallic moeity is moved toward the
D-ring of the steroid, even on a rigid spacer.
Moreover, neutral species (ferrocenyl) are
relatively
well
tolerated
while
cationic
species (ruthenium) decrease the binding
af±nity indicating that the HBD does not
accept a positive change in the 17
α
position
of E
2
. Hence, bulky organometallic moiety
may be tolerated if they localize outside a
zone of steric/electronic constraint.
Coordination
of
selected
transition-
metal
moeities
to
17
α
-alkynylestradiol
may
induce
an
irreversible
(covalent)
binding with the receptor (Fig. 8). Nu-
cleophilic
sulfur
residues
within
or
in
the
close
vicinity
of
the
HBD
are good candidates for the establish-
ment
of
such
a
covalent
bond.
The
key step in this chemical reaction is
the
loss
of
the
17
β
-OH
functional-
ity for the generation of a carbenium
ion;
this
electron-de±cient
center
sta-
bilized by the organometallic fragment
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