Faculty of Agriculture, Kindai University, Nakamachi, Nara 631-8505, Japan.
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
Bioorg Med Chem. 2018 May 1;26(8):1920-1928. doi: 10.1016/j.bmc.2018.02.042. Epub 2018 Feb 27.
HDAC inhibitors enable histones to maintain a high degree of acetylation. The resulting looser state of chromatin DNA may increase the accessibility of DNA drug targets and consequently improve the efficiency of anticancer drugs targeting DNA, such as Topo II inhibitors. A novel class of nucleoside-SAHA derivatives has been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities toward histone deacetylases and Topo II, and their cytotoxicities in cancer cell lines, were evaluated. Among the synthesized hybrid compounds, compound 16b showed the potent HDAC inhibitory activity at a low nanomolar level and exhibited antiproliferative activity toward cancer cell lines including MCF-7 (breast), HCT-116 (colon), and DU-145 (prostate) cancer cells at a low micromolar level. Moreover, compound 16a showed HDAC6-selectivity 20-fold over HDAC1.
HDAC 抑制剂使组蛋白保持高度乙酰化。由此产生的染色质 DNA 更松散的状态可能会增加 DNA 药物靶点的可及性，从而提高针对 DNA 的抗癌药物（如拓扑异构酶 II 抑制剂）的效率。基于拓扑异构酶 II 和组蛋白去乙酰化酶抑制剂的协同抗肿瘤作用，设计并合成了一类新型核苷-SAHA 衍生物。评估了它们对组蛋白去乙酰化酶和拓扑异构酶 II 的抑制活性以及在癌细胞系中的细胞毒性。在所合成的杂合化合物中，化合物 16b 在低纳摩尔水平显示出强效的 HDAC 抑制活性，并在低微摩尔水平显示出对包括 MCF-7（乳腺）、HCT-116（结肠）和 DU-145（前列腺）癌细胞在内的癌细胞系的增殖活性。此外，化合物 16a 对 HDAC6 的选择性是 HDAC1 的 20 倍。
