Syntheses and affinities of novel organometallic-labeled estradiol derivatives: a structure-affinity relationship.
Two series of novel estradiol derivatives, including cationic species, labeled with organometallic fragments Cr(CO)3, Cp*Ru+, or Cp*Rh2+ [Cp* = eta 5-C5(CH3)5] either in the 17 alpha-position or on the A-ring were synthesized, and their relative binding affinities (RBA) for the estradiol receptor were determined. The Ru(II) and the Rh(III) cationic derivatives were obtained as stable salts with the following counter anions (BF4-, PF6-, CF3SO3-). The satisfactory RBA values obtained for most complexes belonging to the 17 alpha series confirm that this position tolerates the presence of bulky neutral species. For instance, complex 4, in which the organometallic fragment Cr(CO)3 was attached to the phenyl ring of the 17 alpha-phenylethynyl fragment, exhibited an RBA value of 24%, very similar to that of the uncomplexed estrogen derivative 3. Surprisingly, the analogous cationic species 6 had no affinity for the estradiol receptor. This unprecedented result shows that the hormone binding site of the estrogen receptor does not tolerate the presence of a positive charge in the 17 alpha-position of the steroid. On the other hand, the alpha-face of the A-ring of estradiol did tolerate positively charged organometallic fragments bearing bulky substituents although the RBA value tended to decrease with increasing charge. The counterion in these cationic derivatives also affected binding affinity. For instance, the Ru(II) species 7a containing an CF3SO3- ion exhibited a reasonable RBA value (5.8%) compared to analogous species 13 with a PF6- ion (RBA of only 0.1%). Moreover, the triflate counteranion preserved the phenolic form of the A-ring of the estrogen derivative whereas the PF6- derivative was unstable and rapidly converted into the dienonylic form in buffer. The compared RBAs of the neutral and cationic species illustrate the preferences of the receptor hormone binding site in accepting or rejecting species of hydrophobic or hydrophilic character.
el Amouri
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Ecole Nationale Supérieure de Chimie de Paris, UA CNRS 403, France.
Vessières
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Vichard
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Top
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Gruselle
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Jaouen
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G
D000818:Animals; D001667:Binding, Competitive; D011232:Chemical Precipitation; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D011479:Protamines; D011959:Receptors, Estradiol / Q000378:metabolism; D012238:Rhodium; D012428:Ruthenium; D012756:Sheep; D013329:Structure-Activity Relationship; D014599:Uterus / Q000378:metabolism
D009942:Organometallic Compounds; D011479:Protamines; D011959:Receptors, Estradiol; D004958:Estradiol; D012428:Ruthenium; D012238:Rhodium