Background: Santacruzamate A (SCA) is a natural product isolated from a marine cyanobacterium. Activity test results revealed that SCA is a highly potent HDAC2 inhibitor with an IC50 value of 0.112 nM. The IC50 of SCA in inhibiting cancer cell proliferation is 28.3 μM and 1.3μM on HCT116 and HuT-78 cells, respectively.

Objective: To develop HDAC inhibitors with improved activity, SCA analogs were synthesized for the Structure-Activity Relationship (SAR) studies.

Methods: Various substituted groups were introduced into the zinc binging group, linker, and cap regions of SCA by various chemical synthetic methods.

Results: Compared with SCA, the derivatives of SCA did not exhibit improved HDAC2 inhibitory activity. Nevertheless, several molecules such as III-32, III-33, IV-4b, and IV-11 showed improved activity in inhibiting cell proliferation on HCT116 and HuT-78 cells.

Conclusion: Collectively, a potent HDAC2 inhibitor SCA was discovered as a lead compound for further development of selective HDAC inhibitors.

背景：Santacruzamate A (SCA) 是一种从海洋蓝藻中分离出来的天然产物。活性测试结果表明，SCA 是一种高效的 HDAC2 抑制剂，IC50 值为 0.112 nM。SCA对HCT116和HuT-78细胞抑制癌细胞增殖的IC50分别为28.3 μM和1.3 μM。

目的：为了开发具有改善活性的 HDAC 抑制剂，合成了 SCA 类似物用于构效关系 (SAR) 研究。

方法：通过各种化学合成方法，将各种取代基团引入SCA的锌结合基团、接头和帽区。

结果：与SCA相比，SCA的衍生物没有表现出提高的HDAC2抑制活性。尽管如此，一些分子如 III-32、III-33、IV-4b 和 IV-11 在抑制 HCT116 和 HuT-78 细胞的细胞增殖方面表现出改善的活性。

结论：总的来说，发现了一种有效的 HDAC2 抑制剂 SCA 作为进一步开发选择性 HDAC 抑制剂的先导化合物。