In order to investigate the possibility of developing diagnostic imaging agents for steroid-positive tumors that are labeled with the readily available radionuclide technetium-99m, we prepared four conjugate systems in which a progestin is linked to a metal chelate system. Three of these are bis-amino bis-thiol (BAT or N2S2) systems and are linked through carbon-21 of progesterone or the 17 alpha- or 11 beta-position of a nortestosterone type progestin. The fourth, an amino-amido-thiol-alcohol chelate (N2OS) system, is linked at the 16 alpha,17 alpha-positions of a dihydroprogesterone. As a model for technetium-labeled complexes, all four chelate systems were converted to their oxo-rhenium complexes. Of the four possible diastereomers in the 16 alpha,17 alpha-system, only one was isolated, while of the four possible diastereomers in the other systems, a syn pair and an anti pair (linker methylene vs rhenium-oxo, relative to the N2S2 plane) were separated in the 17 alpha-substituted series, a syn pair was isolated in the 21-substituted series, and a syn pair and the two individual anti diastereomers were separated in the 11 beta-substituted series. In competitive radiometric receptor binding assays, the 21-, 17 alpha-, and 16 alpha,17 alpha-linked systems had low affinity for the progesterone receptor (less than 0.3% that of promegestone (R5020) or 2% that of progesterone). By contrast, the two anti diastereomers of the 11 beta-linked system had affinities that were 10% and 44% that of R5020 (or 64% and 283% that of progesterone) and the syn pair had an affinity 25% that of R5020 (or 161% that of progesterone). The latter finding indicates that it is possible to prepare metal-labeled steroids that retain high affinity for steroid receptors. These and related systems, when complexed with radioactive metals, may be useful in vivo as receptor-directed agents for diagnostic imaging or therapy of steroid receptor-positive tumors.
We recently reported the dual (antihormonal and cytotoxic) functionality of ferrocifens, which are organometallic complexes derived from hydroxytamoxifen, the standard molecule in the treatment of hormone-dependent breast cancers. To test the hypothesis that the presence of a ferrocenyl substituent on molecules with an affinity for the estrogen receptor is sufficient to give them cytotoxic properties in vitro, we prepared complexes derived from estradiol with a ferrocenyl substituent at positions 7alpha and 17alpha. The complexes thus obtained retain a satisfactory level of affinity for the estrogen receptor (RBA values higher than 12 %). At low concentrations (0.1-1 microM) the complexes show an estrogenic effect in vitro equivalent to that of estradiol on hormone-dependent (MCF-7) breast cancer cells, and no cytotoxic effect on hormone-independent (MDA-MB-231) breast cancer cells. At high concentrations (up to 50 microM) the 17alpha-ethynylferrocenyl estradiol and 7alpha-ferrocenylmethylthio estradiol become cytotoxic (IC(50)=13.2 microM and 18.8 microM, respectively) while the 17alpha-ferrocenylestradiol remains non toxic. The low toxicity of these compounds support our hypothesis that electronic communication between the ferrocenyl and phenol moieties in the hydroxyferrocifens series is a key parameter in the generation of cytotoxic effects at submicromolar concentrations.
We have synthesized six new estrogens substituted at the 11beta-position with a methoxy or vinyl group and at the 17alpha-position with an (E)- or (Z)-chloro/iodovinyl moiety. The products were obtained in good overall yields from the corresponding tri-n-butylstannylvinyl intermediates using the electrophilic halodestannylation methodology. The six new ligands were compared to the 11beta-unsubstituted chloro/iodovinyl derivatives and the 11beta-methoxy (E)- and (Z)-iodovinyl estrogens to evaluate the effects of 11beta-substitution and 20E/Z-stereochemistry. While all the compounds exhibited high affinity for the estrogen receptor, the 20Z-isomers demonstrated higher affinity than the corresponding 20E-isomers. In addition, the presence of the lipophilic 11beta-substituent was favored over either no substituent or a polar (methoxy) group. Within each isomeric series, the presence of the 21-halo substituent had different effects. For the 20E-series, the 21-chloro products had a higher affinity than the 21-iodo analogue, whereas for the 20Z-series the effect was reversed. These results provide additional insights into the interaction of substituted estradiols with the hormone binding domain of the estrogen receptor.
As part our program to probe the molecular requirement for estrogen-receptor binding we undertook the synthesis and evaluation of the 17 alpha,E and 17 alpha,Z halovinyl estradiols. By use of an improved variation of the existing synthetic strategy, the targeted compounds were prepared stereospecifically and in 92-98% yields from the corresponding 17 alpha,E or 17 alpha,Z [(tri-n-butylstannyl)vinyl]estradiol 3-acetates. The novel estradiol derivatives were evaluated for their relative binding affinity (RBA) for the estrogen receptor with use of a rat uterine preparation. The results demonstrated a marked difference between the E and Z isomers and among the halogen employed. The Z isomers possessed significantly higher RBA values and the larger halogens (I, Br) were more effective than the smaller Cl substituent. These results modify the previous interpretations of estrogen-receptor binding for steroidal ligands. As a result, our design of (radio)halogenated ligands will incorporate this concern for Z vs E stereochemistry.
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