Structural Modification Of A Histone Deacetylase Inhibitor D08a To Optimize Its Druglikeness

In February 3,2014, World Health Organization (WHO) published first overview of the global cancer "World Cancer Report 2014" for 6 years. According to UN statistics, in the current global world, each of the 8 death cases dies of cancer, the rate of which is even higher than that of AIDS, tuberculosis and malaria. The report predicted that the global cancer cases would increase from 12,000,000 of 2012 to 24,000,000 of 2035, while the number of cancer deaths might increase from 8,200,000 per year to 12,000,000 after 20 years. Cancer, which is a variety of malignant tumors, is a serious threat to human health, so it is imperative to find efficient, low toxicity and selective anticancer drugs.In recent years, a kind of intracellular metal protease-histone deacetylases (HDACs) have became the new targets for cancer therapy due to their deep relationship with the occurrence and development of tumor. Up to now, USA food and Drug Administration (FDA) has approved 4 histone deacetylase inhibitors (HDACis). In normal cells, HDACs with these inverse function enzyme histone acetyltransferases (HATs) co-regulate the acetylation level of histone as well as some other important proteins; while in cancer cells, over expression of HDACs leads that DNA binds tighter to histone, then preventing the binding between DNA and transcription regulation proteins, such as transcription factors, RNA polymerase and so on. In addition, the over expression of HDACs can also affect other gene functions, such as the chorosome pairing, DNA repair and recombination.At the same time, more and more HDACis show high antitumor activity in vitro and in vivo with multiple antitumor mechanisms, such as inducting the apoptosis and autophagy of tumor cells, inducing the cell cycle arrest of tumor cells, inhibiting angiogenesis of tumor cells, reducing the motility and migration of tumor cells, enhancing the sensitivity of tumor cells to radiotherapy and chemotherapy drug, and reducing the self-repair of DNA.In the previous research of our laboratory, we found a tetrahydroisoquinoline-based HDACi-D08a. Although the activity of D08a was significantly better than that of the listed drug SAHA, it had a poor plasma stability, which made it restricted to the further development to some extent. Therefore, aiming at the defects of the plasma stability of D08a to carry on the corresponding structure optimization, we increase the plasma stability without decreasing activities and strive to find a more suitable candidate for further development. Among the compounds we have synthesized, the enzyme activity and cell activity of compound 9a have been kept, meanwhile its solubility and plasma stability have been significantly improved, leading to the better foundation for the further development of research.