McCague R, Rowlands M G, Grimshaw R, Jarman M
Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, U.K.
Biochem Pharmacol. 1994 Oct 7;48(7):1355-61. doi: 10.1016/0006-2952(94)90557-6.
A ring-fused analogue of tamoxifen, which had previously been shown to have practically identical estrogen receptor (ER) affinity and antitumour potency against estrogen responsive cells as tamoxifen, failed to inhibit calmodulin-dependent cyclic AMP phosphodiesterase. The substitution of an extra methyl group into the ring-fused analogue, at a position which the ethyl group of tamoxifen can occupy in one of its conformations, restored the calmodulin inhibition. Also, the replacement of the tamoxifen ethyl group by methyl diminishes calmodulin inhibition. Direct interaction of these tamoxifen analogues with calmodulin was demonstrated through the use of the fluorescent probe, 2-p-toluidinyl-naphthalene-6-sulfonic acid (TNS). These findings lead to the conclusion that tamoxifen binds to calmodulin in a conformation not accessible to the fused analogue and therefore likely to be different to that which binds to the ER. Also, the results on the ring-fused analogues indicate that the calmodulin binding cannot be essential for antitumour activity.
他莫昔芬的一种稠环类似物，之前已证明其对雌激素受体（ER）的亲和力以及对雌激素反应性细胞的抗肿瘤效力与他莫昔芬几乎相同，但该类似物无法抑制钙调蛋白依赖性环磷酸腺苷磷酸二酯酶。在稠环类似物中，于他莫昔芬的乙基在其一种构象中可占据的位置引入一个额外的甲基，可恢复对钙调蛋白的抑制作用。此外，将他莫昔芬的乙基替换为甲基会减弱对钙调蛋白的抑制作用。通过使用荧光探针2-对甲苯胺基萘-6-磺酸（TNS），证明了这些他莫昔芬类似物与钙调蛋白的直接相互作用。这些发现得出结论，他莫昔芬以一种稠环类似物无法达到的构象与钙调蛋白结合，因此可能与它结合雌激素受体的构象不同。此外，关于稠环类似物的结果表明，钙调蛋白结合对于抗肿瘤活性并非必不可少。
