新型经典 6,5,6-三环苯并[4,5]噻吩并[2,3-d]嘧啶作为胸苷酸合酶和二氢叶酸还原酶双重抑制剂的设计、合成、生物评价及 X 射线晶体结构。
Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.
机构信息
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
出版信息
Bioorg Med Chem. 2011 Jun 1;19(11):3585-94. doi: 10.1016/j.bmc.2011.03.067. Epub 2011 Apr 9.
Abstract
Classical antifolates (4-7) with a tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (±)-9 to ethyl 2-amino-4-methyl-1-benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH₃ substituents inhibited human (h) TS (IC₅₀ =0.26-0.8 μM), but not hDHFR. Substitution of the 2-CH₃ with a 2-NH₂ increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC₅₀ = 0.09-0.1 μM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate.
摘要
经典的抗叶酸类药物（4-7）具有三环苯并[4,5]噻吩[2,3-d]嘧啶骨架和柔性刚性苯甲酰谷氨酸，是胸苷酸合成酶（TS）和二氢叶酸还原酶（DHFR）的双重抑制剂。乙基 2-氨基-4-甲基-4,5,6,7-四氢-1-苯并噻吩-3-羧酸酯（±）-9 的氧化芳构化用 10% Pd/C 转化为乙基 2-氨基-4-甲基-1-苯并噻吩-3-羧酸酯 10 是一个关键的合成步骤。具有 2-CH₃取代基的化合物抑制人（h）TS（IC₅₀=0.26-0.8 μM），但不抑制 hDHFR。用 2-NH₂取代 2-CH₃可使 hTS 抑制作用增加 10 倍以上，同时还能提供出色的 hDHFR 抑制作用（IC₅₀=0.09-0.1 μM）。本研究表明，三环苯并[4,5]噻吩[2,3-d]嘧啶骨架高度有利于单 hTS 或双 hTS-hDHFR 抑制，这取决于 2 位取代基。与 hDHFR 的 X 射线晶体结构 6 和 7 首次揭示，三环 6 和 7 以叶酸结合模式与苯并[4,5]噻吩[2,3-d]嘧啶环结合，噻吩 S 模拟甲氨蝶呤的 4-氨基。
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