Abstract：
Phthalimides are valuable for synthesis and biological properties. New acetamides 3(a-c) and 4(a-c) were synthesized and characterized as precursors for novel N-aminophalimides 5(a-c) and 6(a-c). Structures of 4a, 5(a-b), and 6(a-b) were confirmed by single crystal X-ray. Docking studies identified compounds with favorable Gibbs free energy values for binding to histone deacetylase 8 (HDAC8), an enzyme targeted for anticancer drug development. These compounds bound to both the orthosteric and allosteric pockets of HDAC8, similar to Trichostatin A (TSA), an HDAC8 inhibitor. 6(a-c) contain hydroxyacetamide moiety as a zinc-binding group, a phthalimide moiety as a capping group, and aminoacetamide moiety as a linker group, which are important for ligand-receptor binding. ΔG values indicated that compounds 5b, 6b, and 6c had higher affinity for HDAC8 in the allosteric pocket compared to TSA. In vitro evaluation of inhibitory activities on HDAC8 revealed that compounds 3(a-c) and 5(a-c) showed similar inhibitory effects (IC50 ) ranging from 0.445 to 0.751 μM. Compounds 6(a-c) showed better affinity, with 6a (IC50 = 28 nM) and 6b (IC50 = 0.18 μM) showing potent inhibitory effects slightly lower than TSA (IC50 = 26 nM). These findings suggest that the studied compounds hold promise as potential candidates for further biological investigations.
摘要：
邻苯二胺对合成和生物学性质有价值。合成了新的乙酰胺3（a-c）和4（a-c），并将其表征为新型N-氨基卤化物5（a-c）和6（a-c）的前体。4a的结构，5(a-b),和6(a-b)通过单晶X射线证实。对接研究确定了具有有利的吉布斯自由能值的化合物，用于结合组蛋白脱乙酰酶8（HDAC8），一种靶向抗癌药物开发的酶。这些化合物与HDAC8的正构和变构袋结合，类似于曲古抑菌素A（TSA），HDAC8抑制剂。图6(a-c)含有羟基乙酰胺部分作为锌结合基团，邻苯二甲酰亚胺部分作为封端基团，和氨基乙酰胺部分作为连接基团，这对配体-受体结合很重要。ΔG值表明化合物5b，6b,与TSA相比，6c对变构口袋中的HDAC8具有更高的亲和力。对HDAC8的抑制活性的体外评估显示,化合物3(a-c)和5(a-c)显示出相似的抑制作用(IC50),范围为0.445至0.751μM。化合物6(a-c)具有较好的亲和力,其中6a(IC50=28nM)和6b(IC50=0.18μM)显示出略低于TSA(IC50=26nM)的有效抑制作用。这些发现表明，所研究的化合物有望成为进一步生物学研究的潜在候选者。
