Baqi Younis, Atzler Kerstin, Köse Meryem, Glänzel Markus, Müller Christa E
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
J Med Chem. 2009 Jun 25;52(12):3784-93. doi: 10.1021/jm9003297.
Anthraquinone derivatives related to the moderately potent, nonselective P2Y(12) receptor antagonist reactive blue 2 (6) have been synthesized and optimized with respect to P2Y(12) receptor affinity. A radioligand binding assay utilizing human blood platelet membranes and the P2Y(12) receptor-selective antagonist radioligand [(3)H]2-propylthioadenosine-5'-adenylic acid (1,1-dichloro-1-phosphonomethyl-1-phosphonyl) anhydride ([(3)H]PSB-0413) was applied for compound testing. 1-Amino-2-sulfoanthraquinone derivatives bearing a (p-phenylamino)anilino substitution in the 4-position and an additional acidic function in the meta-position of the aniline ring showed high P2Y(12) receptor affinity. These new anthraquinone derivatives became accessible by a recently developed copper(0)-catalyzed Ullmann coupling reaction of 1-amino-4-bromoanthraquinone derivatives with anilines in phosphate buffer under microwave irradiation. The most potent compounds exhibited K(i) values of 24.9 nM (1-amino-4-[4-phenylamino-3-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, PSB-0739, 39), and 21.0 nM (1-amino-4-[4-phenylamino-3-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, PSB-0702, 41), respectively. 1-Amino-2-sulfo-4-anilinoanthraquinone derivatives appeared to be noncytotoxic, as shown for selected derivatives at two human cell lines (melanoma and astrocytoma). Compounds 39 and 41 represent new lead structures for the development of antithrombotic drugs.
已合成了与中等效力的非选择性P2Y(12)受体拮抗剂活性蓝2（6）相关的蒽醌衍生物，并针对P2Y(12)受体亲和力进行了优化。利用人血小板膜和P2Y(12)受体选择性拮抗剂放射性配体[³H]2-丙硫基腺苷-5'-腺苷酸（1,1-二氯-1-膦酰甲基-1-膦酰）酐（[³H]PSB-0413）的放射性配体结合试验用于化合物测试。在4-位带有（对苯基氨基）苯胺取代且在苯胺环间位带有额外酸性官能团的1-氨基-2-磺基蒽醌衍生物表现出高P2Y(12)受体亲和力。这些新的蒽醌衍生物可通过最近开发的1-氨基-4-溴蒽醌衍生物与苯胺在微波辐射下于磷酸盐缓冲液中进行的铜（0）催化乌尔曼偶联反应制得。最有效的化合物的抑制常数（Ki）值分别为24.9 nM（1-氨基-4-[4-苯基氨基-3-磺基苯基氨基]-9,10-二氧代-9,10-二氢蒽-2-磺酸盐，PSB-0739，39）和21.0 nM（1-氨基-4-[4-苯基氨基-3-羧基苯基氨基]-9,10-二氧代-9,10-二氢蒽-二磺酸盐，PSB-0702，41）。如在两种人类细胞系（黑色素瘤和星形细胞瘤）中对选定衍生物所显示的，1-氨基-2-磺基-4-苯胺基蒽醌衍生物似乎无细胞毒性。化合物39和41代表了抗血栓药物开发的新先导结构。
