el Amouri H, Vessières A, Vichard D, Top S, Gruselle M, Jaouen G
Ecole Nationale Supérieure de Chimie de Paris, UA CNRS 403, France.
J Med Chem. 1992 Aug 21;35(17):3130-5. doi: 10.1021/jm00095a006.
Two series of novel estradiol derivatives, including cationic species, labeled with organometallic fragments Cr(CO)3, CpRu+, or CpRh2+ [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.
合成了两个系列的新型雌二醇衍生物，包括带有有机金属片段Cr(CO)3、CpRu+或CpRh2+ [Cp* = η5-C5(CH3)5] 的阳离子物种，这些片段连接在17α-位或A环上，并测定了它们对雌二醇受体的相对结合亲和力（RBA）。Ru(II)和Rh(III)阳离子衍生物以带有以下抗衡阴离子（BF4-、PF6-、CF3SO3-）的稳定盐形式获得。对于大多数属于17α系列的配合物所获得的令人满意的RBA值证实，该位置能够容忍大体积中性物种的存在。例如，配合物4中有机金属片段Cr(CO)3连接在17α-苯基乙炔基片段的苯环上，其RBA值为24%，与未配位的雌激素衍生物3非常相似。令人惊讶的是，类似的阳离子物种6对雌二醇受体没有亲和力。这一前所未有的结果表明，雌激素受体的激素结合位点不能容忍甾体17α-位存在正电荷。另一方面，雌二醇A环的α-面确实能够容忍带有大体积取代基的带正电荷的有机金属片段，尽管RBA值倾向于随着电荷增加而降低。这些阳离子衍生物中的抗衡离子也影响结合亲和力。例如，含有CF3SO3-离子的Ru(II)物种7a与含有PF6-离子的类似物种13相比，表现出合理的RBA值（5.8%）（后者的RBA仅为0.1%）。此外，三氟甲磺酸盐抗衡阴离子保留了雌激素衍生物A环的酚形式，而PF6-衍生物不稳定，在缓冲液中会迅速转化为二烯酮形式。中性和阳离子物种的RBA比较说明了受体激素结合位点在接受或排斥具有疏水或亲水特性的物种方面的偏好。
