在这项研究中，发现了一系列新型的组蛋白去乙酰化酶6（HDAC6）抑制剂，其中含有多环芳烃环，并对它们的药理活性进行了评估。最有效的化合物10c表现出高水平的HDAC6抑制活性（IC50 = 261 nM）和极佳的HDAC6选择性（HDAC6与HDAC3比值为109）。10c在体外还显示出较好的抗增殖活性，对四种癌细胞株的IC50为7.37-21.84 μM，与tubastatin A（平均IC50 = 6.10 μM）相当。进一步的机制研究发现，10c有效地诱导了B16-F10细胞的凋亡和S期阻滞。此外，在体内外，10c显著增加了乙酰化-α-微管蛋白的表达，而不影响乙酰化H3的水平（HDAC1抑制的标志）。此外，10c（80mg/kg）在黑色素瘤模型中表现出中等的抗肿瘤功效，其肿瘤生长抑制率（TGI）为32.9%，与tubastatin A（TGI = 31.3%）相当。重要的是，10c与我们之前发现的小分子PD-L1抑制剂NP19的联合应用显著降低了肿瘤负荷（TGI% = 60.1%），比单一治疗组更有效。此外，10c与NP19的联合使用增强了抗肿瘤免疫应答，通过降低PD-L1表达水平和增加抗肿瘤CD8 + T细胞在肿瘤组织中的浸润来介导。综上所述，10c代表了一种新型的HDAC6抑制剂，值得进一步研究作为潜在的抗癌药物。

In this study, a novel series of histone deacetylases 6 (HDAC6) inhibitors containing polycyclic aromatic rings were discovered and evaluated for their pharmacological activities. The most potent compound 10c exhibited high HDAC6 inhibitory activity (IC50 = 261 nM) and excellent HDAC6 selectivity (SI = 109 for HDAC6 over HDAC3). 10c also showed decent antiproliferative activity in vitro with IC50 of 7.37-21.84 μM against four cancer cell lines, comparable to that of tubastatin A (average IC50 = 6.10 μM). Further mechanism studies revealed that 10c efficiently induced apoptosis and S-phase arrest in B16-F10 cells. In addition, 10c markedly increased the expression of acetylated-α-tubulin both in vitro and in vivo, without affecting the levels of acetylated-H3 (marker of HDAC1 inhibition). Furthermore, 10c (80 mg/kg) exhibited moderate antitumor efficacy in a melanoma tumour model with a tumour growth inhibition (TGI) of 32.9%, comparable to that (TGI = 31.3%) of tubastatin A. Importantly, the combination of 10c with NP19 (a small molecule PD-L1 inhibitor discovered by us before) decreased tumour burden substantially (TGI% = 60.1%) as compared to monotherapy groups. Moreover, the combination of 10c with NP19 enhanced the anti-tumour immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of anti-tumour CD8+ T cells in tumour tissues. Collectively, 10c represents a novel HDAC6 inhibitor deserving further investigation as a potential anti-cancer agent.