Design and synthesis of novel protein kinase CK2 inhibitors on the base of 4-aminothieno[2,3-d]pyrimidines

  • Eur J Med Chem. 2016 Jun 10:115:148-60. doi: 10.1016/j.ejmech.2016.03.004.
Olga V Ostrynska  1 ,  Anatoliy O Balanda  1 ,  Volodymyr G Bdzhola  1 ,  Andriy G Golub  2 ,  Igor M Kotey  1 ,  Olexander P Kukharenko  1 ,  Andrii A Gryshchenko  1 ,  Nadiia V Briukhovetska  1 ,  Sergiy M Yarmoluk  3
Affiliations
  • 1. Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, 150 Zabolotnogo Str., 03680 Kyiv, Ukraine.
  • 2. Otava Ltd, 400 Applewood Crescent, Unit 100, Vaughan, Ontario L4K 0C3, Canada.
  • 3. Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, 150 Zabolotnogo Str., 03680 Kyiv, Ukraine. Electronic address: [email protected].
PMID: 27017545 DOI: 10.1016/j.ejmech.2016.03.004
Abstract

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.

Keywords
Aminothieno[2,3-d]pyrimidine; Docking; Drug design; Inhibitor; Intramolecular hydrogen bond; Protein kinase CK2.
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