Xie Rui, Shi Jinghua, Qu Yue, Tang Pingwah, Wu Xinying, Yang Ming, Yuan Qipeng
College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
Med Chem. 2015;11(7):636-48. doi: 10.2174/1573406411666150429154107.
A facile and atom-economical boric acid catalyzed direct amidation without any coupling agents for the preparation of Suberoylanilide Hydroxamic Acid (SAHA) and SAHA-based inhibitors targeting anti-proliferation of cancer cells is described. It is applicable to the preparation of SAHA-based inhibitors having an unprotected hydroxyl group in the phenyl ring without the need of the protection. The in-vitro assays data indicate that the nature and the position of the substituents (activating and/or deactivating) in the capping group (phenyl ring) of SAHA-based inhibitors synthesized in this study have a vital impact on the potency of anti-proliferative activity against cancer cells. With low toxicity toward the normal cells, a number of synthesized SAHA-based inhibitors with two substituents in the phenyl ring possess higher antiproliferative activity than SAHA and Cisplatin toward six studied cancer cell lines: A375 human skin cancer cells, A549 human lung cancer cells, MGC80-3 human gastric cancer cells, H460 human lung cancer cells, H1299 human lung cancer cells, and HepG2 human liver cancer cells. Cisplatin is a common chemotherapeutic drug with high cytotoxicity for a variety of cancer treatments. The inhibitors provided in this study might signify future therapeutic drugs for cancer treatment.
本文描述了一种简便且原子经济的硼酸催化直接酰胺化反应，无需任何偶联剂即可制备伏立诺他（SAHA）以及靶向癌细胞抗增殖的基于SAHA的抑制剂。该方法适用于制备苯环上具有未保护羟基的基于SAHA的抑制剂，无需进行保护。体外试验数据表明，本研究中合成的基于SAHA的抑制剂的封端基团（苯环）中取代基（活化和/或钝化）的性质和位置对其对癌细胞的抗增殖活性效力有至关重要的影响。一些在苯环上有两个取代基的合成的基于SAHA的抑制剂对正常细胞毒性低，对六种研究的癌细胞系：A375人皮肤癌细胞、A549人肺癌细胞、MGC80 - 3人胃癌细胞、H460人肺癌细胞、H1299人肺癌细胞和HepG2人肝癌细胞，具有比SAHA和顺铂更高的抗增殖活性。顺铂是一种常见的化疗药物，对多种癌症治疗具有高细胞毒性。本研究提供的抑制剂可能预示着未来用于癌症治疗的药物。
