Design, Synthesis And SAR Analysis Of Novel HDAC Inhibitors With Anti-cancer Activities

Tumor, as a global public health problem, has become one of serious threats to human, second only to the cardia-cerebrovascular disease. The tumor formation and development is a complicated process, however the relationship between the tumor and abnormal gene expression has been widely reported, especially those proteins involved in epigenetic regulations. The overexpression of HDACs has been found in a wide variety of cancers and plays a significant role in promoting tumorigenesis and development.HDAC inhibitors (HDACis), as a kind of inhibitors that target HDACs, perform significant antitumor effects and show diverse antitumor mechanisms. Up to now three drugs have been approved by the FDA:SAHA、FK-228 and PXD-101. In addition, over 20 inhibitors are now being in clinical trials. All these results indicated that the research and development of novel HDACis has broad market prospects.It is well known that tumor metastasis is one of the important factors which is responsible for cancer deaths, therefore the research and development of novel HDACis with anti-metastatic activity may be more effective in the treatment of cancer. Structural modification on the Cap region is proven to be an effective strategy in order to develop novel HDAC inhibitors, therefore insertion of the pharmacophore with anti-metastatic activities into the Cap region of classic HDAC inhibitors would be regarded as one of feasible strategies for creating novel HDAC inhibitors.It was reported that CK-548 was one inhibitor targeting Arp2/3 complex, which can insert into the hydrophobic region of Arp3 and influence the formation of microtubule. In order to develop the novel HDAC inhibitors with anti-metastatic activity of our compounds, the pharmacophore of CK-548 was incorporated into the Cap region of classic HDAC inhibitors and formed two new series of HDAC is. More than 200 compounds were designed and synthesized, which were followed evaluated by several comprehensive biological tests. Firstly nuclear exact was used which mainly contains HDACs 1 and 2 as the enzyme source to test target compounds, some compounds with good enzyme inhibitory activites were continued to be evaluated on cell assays and in vivo mouse xenograft models. At last compound 13b was found to perform much better anti-proliferation and anti-metastatic activities than SAHA both in vitro and in wo.In summary, HDACs, as one of potential antitumor targets, were selected to study in the field of anti-tumor. More than 200 new HDACis were synthesized via the methods that combination of medicinal chemistry, molecular biology and computational chemistry. All the target compounds were detected via enzymes assays and novel compounds with good activities were further tested in vitro anti-proliferative and anti-metastatic assays and the most potent compound was at last tested in vivo animal models. Our study found over ten compounds possessed better anti-pro liferative activities than the approved drug SAHA. And most importantly, many of these compounds showed prominent anti-metastatic activities, which also validated our original design idea.