Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, China.
Bioorg Med Chem. 2020 Sep 1;28(17):115639. doi: 10.1016/j.bmc.2020.115639. Epub 2020 Jul 10.
Histone deacetylases (HDACs) have been found to be biomarkers of cancers and the corresponding inhibitors have attracted much attention these years. Herein we reported a near-infrared fluorescent HDAC inhibitor based on vorinostat (SAHA) and a NIR fluorophore. This newly designed inhibitor showed similar inhibitory activity to SAHA against three HDAC isoforms (HDAC1, 3, 6). The western blot assay showed significant difference in compared with the negative group. When used as probe for further kinematic imaging, Probe 1 showed enhanced retention in tumor cells and the potential of HDAC inhibitors in drug delivery was firstly brought out. The cytotoxicity assay showed Probe 1 had some anti-proliferation activities with corresponding IC values of 9.20 ± 0.96 μM on Hela cells and 5.91 ± 0.57 μM on MDA-MB-231 cells. These results indicated that Probe 1 could be used as a potential NIR fluorescent in the study of HDAC inhibitors and lead compound for the development of visible drugs.
组蛋白去乙酰化酶 (HDACs) 已被发现是癌症的生物标志物，相应的抑制剂近年来受到了广泛关注。在此，我们报道了一种基于伏立诺他 (SAHA) 和近红外荧光团的近红外荧光 HDAC 抑制剂。这种新设计的抑制剂对三种 HDAC 同工酶 (HDAC1、3、6) 的抑制活性与 SAHA 相似。Western blot 分析表明，与阴性对照组相比，该抑制剂具有显著差异。当用作进一步的动力学成像探针时，探针 1在肿瘤细胞中的保留增强，首次提出了 HDAC 抑制剂在药物传递中的潜力。细胞毒性试验表明，探针 1对 Hela 细胞的相应 IC 值为 9.20±0.96 μM，对 MDA-MB-231 细胞的 IC 值为 5.91±0.57 μM，具有一定的抗增殖活性。这些结果表明，探针 1可以用作 HDAC 抑制剂研究中的潜在近红外荧光探针和可见药物开发的先导化合物。
