基于4-氨基噻吩并[2,3-d]嘧啶设计与合成新型蛋白激酶CK2抑制剂
Design and synthesis of novel protein kinase CK2 inhibitors on the base of 4-aminothieno[2,3-d]pyrimidines.
作者信息
Ostrynska Olga V, Balanda Anatoliy O, Bdzhola Volodymyr G, Golub Andriy G, Kotey Igor M, Kukharenko Olexander P, Gryshchenko Andrii A, Briukhovetska Nadiia V, Yarmoluk Sergiy M
机构信息
Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, 150 Zabolotnogo Str., 03680 Kyiv, Ukraine.
Otava Ltd, 400 Applewood Crescent, Unit 100, Vaughan, Ontario L4K 0C3, Canada.
出版信息
Eur J Med Chem. 2016 Jun 10;115:148-60. doi: 10.1016/j.ejmech.2016.03.004. Epub 2016 Mar 9.
An extension of our previous research work has resulted in a number of new ATP-competitive CK2 inhibitors that have been identified among 4-aminothieno[2,3-d]pyrimidine derivatives. The most active compounds obtained in the course of the research are 3-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5e (NHTP23, IC50 = 0.01 μM), 3-(5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5g (NHTP25, IC50 = 0.065 μM) and 3-(6-methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5n (NHTP33, IC50 = 0.008 μM). Structure-activity relationships of the tested 4-aminothieno[2,3-d]pyrimidine derivatives have been studied and their binding mode with ATP-acceptor site of CK2 has been proposed. A negative effect of intramolecular hydrogen bonding in the compounds' structure is discussed.
我们之前研究工作的拓展已产生了一些新的ATP竞争性CK2抑制剂，这些抑制剂是在4-氨基噻吩并[2,3-d]嘧啶衍生物中鉴定出来的。在该研究过程中获得的活性最高的化合物是3-(5-对甲苯基-噻吩并[2,3-d]嘧啶-4-基氨基)-苯甲酸，5e（NHTP23，IC50 = 0.01 μM）、3-(5-苯基-噻吩并[2,3-d]嘧啶-4-基氨基)-苯甲酸，5g（NHTP25，IC50 = 0.065 μM）以及3-(6-甲基-5-苯基-噻吩并[2,3-d]嘧啶-4-基氨基)-苯甲酸，5n（NHTP33，IC50 = 0.008 μM）。已研究了所测试的4-氨基噻吩并[2,3-d]嘧啶衍生物的构效关系，并提出了它们与CK2的ATP受体位点的结合模式。讨论了化合物结构中分子内氢键的负面影响。
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