Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, Spain.
J Med Chem. 2012 Nov 26;55(22):9467-91. doi: 10.1021/jm300618u. Epub 2012 Oct 17.
A SAR study has been carried out around a modified scaffold of the natural product psammaplin A obtained by replacing the o-bromophenol unit by an indole ring. A series of indole psammaplin A constructs were generated in a short synthetic sequence that starts with the functionalization of the C3 indole position with in situ generated nitrosoacrylate, and this is followed by protection of the β-indole-α-oximinoesters, saponification, condensation with symmetrical diamines, and deprotection. Biochemical and cellular characterization using U937 and MCF-7 cells confirmed that many of these analogues displayed more potent actitivies than the parent natural product. Moreover, in addition to the reported HDAC and DNMT dual epigenetic inhibitory profile of the parent compound, some analogues, notably 4a (UVI5008), also inhibited the NAD(+)-dependent SIRT deacetylase enzymes. The SAR study provides structural insights into the mechanism of action of these multiple epigenetic ligands and paves the way for additional structural exploration to optimize their pharmacological profiles. Because of their multi(epi)target features and their action in ex vivo samples, the indole-based psammaplin A derivatives are attractive molecules for the modulation of epigenetic disorders.
已围绕天然产物 psammaplin A 的改良支架进行 SAR 研究，该支架通过将邻溴苯酚单元替换为吲哚环来获得。通过在原位生成的亚硝基丙烯酰胺对 C3 吲哚位置进行功能化，随后保护β-吲哚-α-肟酯、皂化、与对称二胺缩合以及脱保护，在短的合成序列中生成了一系列吲哚 psammaplin A 构建体。使用 U937 和 MCF-7 细胞进行的生化和细胞特性分析证实，许多这些类似物的活性比母体天然产物更强。此外，除了母体化合物报告的具有 HDAC 和 DNMT 双重表观遗传抑制作用外，一些类似物，特别是 4a（UVI5008），还抑制了 NAD(+)-依赖性 SIRT 脱乙酰酶。这项 SAR 研究为这些多表观遗传配体的作用机制提供了结构见解，并为进一步的结构探索以优化它们的药理学特性铺平了道路。由于它们的多（表观遗传）靶点特征及其在体外样本中的作用，基于吲哚的 psammaplin A 衍生物是调节表观遗传紊乱的有吸引力的分子。
