新型尿嘧啶连接席夫碱作为具有凋亡潜力的双功能II型组蛋白去乙酰化酶/ I型拓扑异构酶抑制剂的设计与合成
Design and synthesis of novel uracil-linked Schiff bases as dual histone deacetylase type II/topoisomerase type I inhibitors with apoptotic potential.
作者信息
El-Kalyoubi Samar, Elbaramawi Samar S, Eissa Ahmed G, Al-Ageeli Essam, Hobani Yahya Hasan, El-Sharkawy Aya Ali, Mohamed Hossam Taha, Al-Karmalawy Ahmed A, Abulkhair Hamada S
机构信息
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Port Said University, Port Said, 42511, Egypt.
Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
出版信息
Future Med Chem. 2023 Jun;15(11):937-958. doi: 10.4155/fmc-2023-0112. Epub 2023 Jun 29.
The previously reported dual histone deacetylase type II (HDAC II) / topoisomerase type I (Topo I) inhibitors suffer pharmacokinetic limitations because of their huge molecular weights. We report the design and synthesis of a smarter novel set of uracil-linked Schiff bases () as dual HDAC II/Topo I inhibitors keeping the essential pharmacophoric features. Cytotoxicity of all compounds was assessed against three cancer cell lines. Studies of their effects on the apoptotic and antiapoptotic genes, molecular docking studies, and absorption, distribution, metabolism and excretion studies were conducted. Compounds and exhibited significant activities. The bromophenyl derivative displayed the best selectivity index, with IC values against HDAC II and Topo I of 1.12 and 13.44 μM, respectively. Compound could be considered a lead HDAC II/Topo I inhibitor.
先前报道的双组蛋白去乙酰化酶II型（HDAC II）/拓扑异构酶I型（Topo I）抑制剂由于分子量巨大而存在药代动力学限制。我们报道了一组更智能的新型尿嘧啶连接席夫碱（）作为双HDAC II/Topo I抑制剂的设计与合成，保留了关键的药效基团特征。评估了所有化合物对三种癌细胞系的细胞毒性。进行了它们对凋亡和抗凋亡基因影响的研究、分子对接研究以及吸收、分布、代谢和排泄研究。化合物和表现出显著活性。溴苯基衍生物显示出最佳的选择性指数，其对HDAC II和Topo I的IC值分别为1.12和13.44 μM。化合物可被视为一种先导性HDAC II/Topo I抑制剂。
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