Antitumor Steroids
441
Fig. 1
Chemical formula of
estramustine
phosphate (Estracyt).
O
P
ONa
ONa
O
(Cl-CH
2
-CH
2
)
2
-N-C-O
O
(receptor-positive vs receptor-negative cell
lines) precluding their potential testing in
clinical trials. Metabolistic instability of
compounds also precludes their use. In
fact, out of the hundreds of compounds
synthesized, estramustine phosphate (Es-
tracyt) (Fig. 1) is the only one having a
place in the therapeutic arsenal (treatment
of advanced prostatic cancer).
The growing number of experimentally
determined crystal structures of ligand-
binding
domains
of
steroid
hormone
receptors provided a theoretical basis for
the synthesis of a new generation of
cytotoxic-linked steroids having a chance
to associate with their cognate receptor.
It
is
our
purpose
to
focus
on
this
topic. First, we will rapidly describe the
structural determinants that govern the
interactions of a ligand with its receptor,
with special emphasis on estrogens and
antiestrogens.
Major
advances
in
the
synthesis of cytotoxic-linked estrogens in
comparison with other classes of steroids
justify this option. Next, we will move to
the description of estrogen derivatives with
potential antitumor activity.
2
Steroid Hormone Receptors
2.1
Structure and Conformation of the
Hormone Binding Domains
Steroid hormone receptors are members of
a superfamily of nuclear receptors, which
regulate the expression of gene involved
in cell proliferation and/or differentia-
tion. All these receptors encode various
domains with speci±c functions (A/B,
C, D, E, and F; Fig. 2). The N-terminal
A/B domain of each receptor contains
a ligand-independent activation function
(AF-1) required for the transcriptional
activation of target genes. The adjacent C-
domain contains two zinc ±ngers, which
play an important role in DNA sequence-
speci±c bindings (association with speci±c
response elements). The D-domain is a
hinge region, which separates ABC do-
mains from the hormone binding domain
(HBD; domain E). This binding domain
contains
a
ligand-dependent
activation
function (AF-2) located in its carboxy-
terminal part, a third additional AF-site
located on the amino-terminal part of the
HBD has been reported in the gluco and es-
trogen receptors (AF-2b). The C-terminal
part of the receptors (end of domain E
and F) is involved in the regulation of
their half-life (proteolysis) and transcrip-
tional activity.
Binding of a steroidal hormone to its re-
ceptor always provokes a conformational
change in the latter that allows, ultimately,
the transcription of target genes. Receptor
molecules, in homo- and heterodimeric
associations, exert their transcriptional ef-
fect through interaction with response
elements located in the promoter region of
these genes; alternatively, they may operate
via their interaction with other classes of
DNA-bound transcription factors (i.e. AP1,
