Incorporating a DNA-binding fragment in HDAC inhibitors has been proved to be an effective strategy for the treatment of hematologic malignancies by our group. However, similar to other approved HDAC inhibitors, their effects on solid tumor were poor. For this issue, a series of 2,5-diphenyl-1,3,4-thiadiazole hydroxamate derivatives were designed and synthesized as the HDAC inhibitors with DNA binding affinity. Among the target compounds, 4j not only bound with DNA effectively but also exhibited the most potent inhibitory activity against HDAC1 with the IC₅₀ of 15 nM. Compared to SAHA, compound 4j displayed stronger antiproliferative activity in tested tumor cell lines. Western blot analysis showed that 4j could enhance the acetylation of histone H3 and α-tubulin, as well as promote the activation of caspase 3 in HCT116 and MC38 cell lines. Furthermore, these responses resulted in significant suppression of tumor growth in the MC38 tumor model. This work validated that compound 4j was a promising lead compound for further structural optimization.

我们小组已证明在 HDAC 抑制剂中掺入 DNA 结合片段是治疗血液系统恶性肿瘤的有效策略。然而，与其他已获批准的 HDAC 抑制剂类似，它们对实体瘤的作用很差。针对这一问题，设计并合成了一系列2,5-二苯基-1,3,4-噻二唑异羟肟酸酯衍生物作为具有DNA结合亲和力的HDAC抑制剂。在目标化合物中，4j不仅与DNA有效结合，而且对HDAC1表现出最有效的抑制活性，IC ₅₀为15 nM。与 SAHA 相比，化合物4j在测试的肿瘤细胞系中显示出更强的抗增殖活性。Western印迹分析表明，4j可以增强组蛋白 H3 和 α-微管蛋白的乙酰化，并促进 HCT116 和 MC38 细胞系中 caspase 3 的活化。此外，这些反应导致 MC38 肿瘤模型中肿瘤生长的显着抑制。这项工作验证了化合物4j是一种有前途的先导化合物，可用于进一步的结构优化。