Design, Synthesis And Anti-tumor Activity Evaluation Of Benzylpyrimidine Hydroxamic Acid Derivatives

Tumor is a kind of multi-gene related diseases. For the past decades, targeted inhibitors are increasingly popular and tons of small molecular inhibitors have been prepared. Although the initial activities were satisfactory, application of some inhibitors were, to some extent, limited by their drug resistance, side effects or low susceptibility. Combination or inhibitors targeting multiple pathways might be promising in the fields of cancer therapy and in dealing with these problems. In addition, a lot of studies have been down to combine histone deacetylase (HDAC) inhibitors and epidermal growth factor receptor inhibitors (EGFRi) to overcome the latter acquired drug resistance; loads of efforts have been made to improve the low susceptibility and reduce toxicity. The results of these cases were practically admirable.HDAC can regulate gene transcription by changing chromatin configuration. If the disorder of enzyme activity occurs, the equilibrium of cell gene expression will be broken and expression of a series of regulators in the processes of cell cycle and cell proliferation will be out of balance, eventually leading to cancer. HDACs inhibitors (HDACi) can effectively inhibit the growth of tumor cells, inducing terminal differentiation and apoptosis of cancer cells and play vital roles in the field of tumor treatment. Vorinostat (SAHA) was approved by the US FDA in 2006 to treat cutaneous T-cell lymphoma (CTCL). Phase â… /â…¡ clinical results showed, however, that the activities of pan-inhibitor SAHA against for some solid tumors was limited by its side effects and low response. It has been confirmed that CDKs inhibitors could reduce the side effects caused by HDACs inhibitors.CDKs are a class of Ser/Thr kinases. Abnormalities of cell cycle are universally observed in various human cancers. There are more than 20 members in CDK family. They not only play a vital role in cell cycle regulation and neuronal differentiation, but also act as an important regulators of transcription.In this report, we designed and synthesized a series of benzylpyrimidine hydroxamic acid derivatives as dual inhibitors based on the pharmacophore characteristics of both HDACi and CDK inhibitor. We synthesized key intermediates from aryl methyl ketones via multiple step nucleophilic addition-eliminate, nucleophilic substitution and oxidation reaction. Then, the target compounds were obtained after dealing with hydroxylamine potassium solution at ambient-temperature. In this paper, a total of 55 new compounds were designed and synthesized, including 28 target compounds and 27 intermediates.According to the preliminary evaluation in vitro, many of these compounds exhibited similar or higher HDAC inhibition activities than SAHA, and some showed good inhibitory potency against CDK9. Antiproliferative assay with MTT showed that certain compounds had significant anti-proliferactive effects, especially 7e,7g,7h and 71. To the test of most cancer cell, these compounds exhibited much better potency than SAHA (HDAC inhibitor) with IC50 value for submicromole, and some even higher than compound 30 (CDK inhibitor). Benzylpyrimidine hydroxamic acid analogues designed in this report practically showed dramatic anti-proliferative activities because of their multiple targeting. So, the inhibitors targeting multiple pathways might become important strategy in the treatment of cancer.