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R. S. Muthyala et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4485–4488
For Type I ligands, it is intriguing to note that the
binding affinity depends on the position of the bridge.
For compound 13, in which the bridge is para to the
hydroxyl group, the binding affinity is higher than in
compound 12, in which the bridge is meta to the phe-
nolic hydroxyl group. Another feature that is readily
apparent from the SAR study for Type I ligands is that
ER does not seem to tolerate any substituent, electron
donating or withdrawing, on the periphery of the
bicyclic core. For example, note the significantly
reduced binding affinities of both 16 and 28, compared
to 12 and 13, respectively.
selectivity. It remains to be seen whether this selectivity
and affinity can be further enhanced by the addition of a
polar functionality on the bicyclic core to mimic the
distal ring-OH group of E2. Studies in this direction will
be the subject of future investigations and will be
reported in due course.
Acknowledgements
This research was supported by grants from the
National Institutes of Health (PHS 5R37 DK15556).
Compounds containing phenols directly attached to the
bicyclic core (Type II ligands) exhibit higher affinity
toward ER compared to Type I ligands. Presumably,
this is in part due to their increased flexibility. What is
noteworthy, however, is that some of the Type II
ligands (20 and 21) have significant ERb affinity selec-
tivity. Monophenol 20 exhibits a 15-fold selectivity for
ERb which is further increased by the introduction of a
methyl group at C-9 as in 21. The ERb binding selec-
tivity of 21 is comparable to some of the recently
reported triazines.19 Bisphenols 24 and 25 have lower
binding affinities and exhibit little or no binding selec-
tivity for ERb. Preliminary data shows that compound
21 does not exhibit substantial selectivity for ERb in cell
based transfection assays, either in terms of efficacy or
potency (S. Sheng and B. S. Katzenellenbogen, unpub-
lished). During the preparation of this manuscript, we
became aware of another report pertaining to the
synthesis of non-steroidal ligands having bicyclo[3.3.1]-
nonane cores.20 However, the binding affinities and the
ERb, selectivities of the ligands described in that report
are lower than those of compound 21.
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Of the various ligands investigated in this study, type III
ligands exhibit the highest affinity for ER. Remarkably,
unlike a similar substitution in the type II series, the
replacement of a methyl group in 26 with another phe-
nol leads to a very high affinity ligand (compound 27),
having an RBA of 500% of that of E2. In fact, this
binding affinity is almost twice that of the well-known
estrogen cyclofenil (RBA: ERa=68 and ERb=334),
which is similar in all respects to 27 except for the three
carbon bridge. This indicates that for certain types of
structures, the binding affinity of a ligand can be
increased simply by an increase in the number of
hydrophobic interactions through the introduction of a
bicyclic core. Interestingly, Type III ligands derived
from other three-dimensional cores having a larger or
smaller number of carbon atoms showed reduced affi-
nity for ER. We have conducted and reported elsewhere
a detailed structure–activity study of Type III ligands.21
20. Sibley, R.; Hatoum-Mokdad, H.; Schoenleber, R.; Musza,
L.; Stirtan, W.; Marrero, D.; Carley, W.; Xiao, H.; Dumas, J.
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nellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem.
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In conclusion, by examining three novel structural
motifs as E2 mimics, we identified Type III ligands as
lead compounds for developing high-affinity ER
ligands. Type II ligands show significant ERb affinity