Dobrydneva Yuliya, Williams Roy L, Katzenellenbogen John A, Ratz Paul H, Blackmore Peter F
Division of Pharmacology, Department of Physiological Sciences, Eastern Virginia Medical School, P.O. Box 1980, 700 Onley Road, Norfolk, VA 23501, USA.
Thromb Res. 2003 Apr 15;110(1):23-31. doi: 10.1016/s0049-3848(03)00110-5.
The effects of compounds with the stilbene pharmacophore [diethylstilbestrol (DES), DES derivatives, tetrahydrochrysene (THC), and THC derivatives] were examined for their ability to inhibit thrombin-induced Ca(2+) influx in human platelets. DES derivatives (DES dimethyl ether, DES dipropionate, dienestrol, and hexestrol) had lower inhibitory activity than DES. Esterification of DES with the bulky monobenzyl group eliminated inhibitory activity. Unsubstituted THC diol had the lowest inhibitory activity in the series of the THC derivatives bearing substituents in the 5,11 positions. These derivatives, either diethyl or dipropyl, cis or trans, were potent inhibitors of thrombin-induced Ca(2+) elevation (near 100% inhibition at 10 microM). Therefore, stilbene pharmacophore having bulk out of the plane of the double bond (from the twisting of the two aromatic rings or from addition of all substituents) seems to be requirement for the inhibitory activity. Free hydroxyl groups are also required for inhibitory activity, most likely for hydrogen bonding, since trans-diethyl tetrahydrochrysene dimethyl ether was inactive. Compounds bearing ethyl substituents (DES and THC derivatives) inhibited thrombin-induced release of calcium from the endoplasmic reticulum. These compounds also inhibited thapsigargin-induced Ca(2+) influx. This result implies that these compounds also block store-operated Ca(2+) influx directly, as well as internal Ca(2+) release. Compounds without ethyl substituents (trans-resveratrol, genistein, daidzein, and THC diol) only inhibited calcium influx into platelets.
研究了具有芪药效基团的化合物[己烯雌酚（DES）、DES衍生物、四氢并四苯（THC）和THC衍生物]抑制凝血酶诱导人血小板Ca(2+)内流的能力。DES衍生物（DES二甲醚、DES二丙酸酯、己二烯雌酚和己烷雌酚）的抑制活性低于DES。用庞大的单苄基对DES进行酯化消除了抑制活性。在5,11位带有取代基的THC衍生物系列中，未取代的THC二醇具有最低的抑制活性。这些衍生物，无论是二乙基还是二丙基，顺式或反式，都是凝血酶诱导的[Ca(2+)]i升高的有效抑制剂（在10 microM时接近100%抑制）。因此，在双键平面外具有体积（由于两个芳香环的扭曲或所有取代基的添加）的芪药效基团似乎是抑制活性的必要条件。抑制活性也需要游离羟基，很可能是用于氢键形成，因为反式二乙基四氢并四苯二甲醚没有活性。带有乙基取代基的化合物（DES和THC衍生物）抑制凝血酶诱导的内质网钙释放。这些化合物也抑制毒胡萝卜素诱导的Ca(2+)内流。这一结果表明，这些化合物还直接阻断了储存-操作性Ca(2+)内流以及细胞内Ca(2+)释放。没有乙基取代基的化合物（反式白藜芦醇、染料木黄酮、大豆苷元和THC二醇）仅抑制钙流入血小板。
