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抑制剂可使组蛋白保持高度乙酰化。染色质DNA产生的较松散状态可以增加DNA药物靶标的可及性，从而提高靶向DNA的抗癌药物（如Topo II抑制剂）的效率。基于拓扑异构酶II和组蛋白脱乙酰基酶抑制剂的协同抗肿瘤作用，设计和合成了一类新型的核苷-SAHA衍生物。评估了它们对组蛋白脱乙酰基酶和Topo II的抑制活性，以及​​它们在癌细胞系中的细胞毒性。在合成的杂化化合物中，化合物16b在低纳摩尔水平下显示出有效的HDAC抑制活性，并在低微摩尔水平下表现出对癌细胞系（包括MCF-7（乳腺癌），HCT-116（结肠）和DU-145（前列腺）癌细胞）的抗增殖活性。此外，化合物16a的HDAC6-选择性是HDAC1的20倍。