Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
J Med Chem. 2010 Apr 22;53(8):3320-9. doi: 10.1021/jm100047k.
Selective estrogen receptor (ER) down-regulators (SERDs) reduce ERalpha protein levels as well as block ER activity and therefore are promising therapeutic agents for the treatment of hormone refractory breast cancer. Starting with the triarylethylene acrylic acid SERD 4, we have investigated how alterations in both the ligand core structure and the appended acrylic acid substituent affect SERD activity. The new ligands were based on high affinity, symmetrical cyclofenil or bicyclo[3.3.1]nonane core systems, and in these, the position of the carboxyl group was extended from the ligand core, either retaining the vinylic linkage of the substituent or replacing it with an ether linkage. Although most structural variants showed binding affinities for ERalpha and ERbeta higher than that of 4, only the compounds preserving the acrylic acid side chain retained SERD activity, although they could possess varying core structures. Hence, the acrylic acid moiety of the ligand is crucial for SERD-like blockade of ER activities.
选择性雌激素受体（ER）下调剂（SERD）降低 ERalpha 蛋白水平，并阻断 ER 活性，因此是治疗激素难治性乳腺癌的有前途的治疗剂。从三芳基乙烯丙烯酸 SERD 4 开始，我们研究了配体核心结构和附加的丙烯酸取代基的变化如何影响 SERD 活性。新的配体基于高亲和力的对称环己芬或双环[3.3.1]壬烷核心系统，在这些系统中，羧基的位置从配体核心延伸，保留取代基的乙烯基键或用醚键取代它。尽管大多数结构变体对 ERalpha 和 ERbeta 的结合亲和力高于 4，但只有保留丙烯酸侧链的化合物保留了 SERD 活性，尽管它们可以具有不同的核心结构。因此，配体的丙烯酸部分对于 ER 活性的 SERD 样阻断至关重要。
