Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom.
J Med Chem. 2012 Feb 23;55(4):1731-50. doi: 10.1021/jm2016182. Epub 2012 Feb 9.
Psammaplin A (11c) is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that 11c functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC(50) 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7, and W138 cells, with the SAR of cytotoxicity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation but little effect on tubulin acetylation. Finally, we have found no evidence for 11c functioning as a DNMT inhibitor.
沙麦巴林 A（11c）是一种海洋代谢产物，先前被报道为两种表观遗传酶：组蛋白去乙酰化酶和 DNA 甲基转移酶的有效抑制剂。已经设计并合成了基于沙麦巴林 A 核心的聚焦文库，以探究该分子负责其活性的分子特征。通过还原二聚体沙麦巴林支架后产生的游离巯基的直接体外测定，我们明确证明 11c 作为天然前药起作用，其还原形式对体外 HDAC1 具有高活性（IC500.9 nM）。此外，我们已经证明它具有高同工酶选择性，对 HDAC1 的选择性是 HDAC6 的 360 倍，对 HDAC7 和 HDAC8 的活性低 1000 倍以上。围绕我们的聚焦文库进行的 SAR 揭示了许多特征，最显著的是肟官能团对这种选择性很重要。许多化合物在 A549、MCF7 和 W138 细胞中表现出显著的细胞毒性，细胞毒性的 SAR 与 HDAC 抑制相关。此外，化合物处理导致组蛋白乙酰化的上调，但对微管蛋白乙酰化几乎没有影响。最后，我们没有发现 11c 作为 DNMT 抑制剂起作用的证据。
