Structure Modification And Antitumor Activity Study Of (S)-4-(2-AMINO-2- Phenylacetamido)-N-Hydroxybenzamide

In recent years, a class of intracellular metalloproteases, which are named as histone deacetylases (HDACs) because of the function of catalysing the removal of acetyl groups from lysine residues in histone amino termini, has become popular targets for cance therapyr. HDACs play important roles in the modification of chromatin structure and regulation of gene expression. Actually, HDACs family consists of diverse metalloproteases existing widely in eukaryotic cell. By now, eighteen HDACs, subdivided into four classes, have been identified in human. Cooperating with histone acetyltransferases (HATs), the inverse function enzyme, HDACs can adjust the posture of chromatin and regulate the expression of DNA. The dysregulation of histone expression and function could lead to kinds of pathological changes, one of which is cancer. Because of this reason, the research and development of histone deacetylase inhibitors have become one of the most popular contents in the field of cancer therapy.With the fast development of computing technology, the application of computers in the field of drug discovery has become much more common. By using the method of virtue screening, our group found an interesting compound that exhibited inhibition to histone deacetylase from the commercial compound databank. After the modification according to the bioisostere theory, skeleton D was proposed to be potential to find new histone deacetylase inhibitors. In this issue,30 derivatives, fell into four series, were synthesized from the structure of skeleton D. For N series, ureido group, the linking part between substituted phenyl ring and the initial skeleton, is supposed to interact with the residues on the surface of HDAC protein by H-bond. Benzamide is replaced with cinnamamide for R series in order to adjust the length of the linking part. P series are reformed from the lead compound, D3, to explore the difference between aromatic heterocycte and aromatic ring. We chose methylamino group as linking group for X series in order to adjust logP to make the compound absorbed better. The structures of all compounds have been confirmed by ESI-MS and NMR.After the bioactivity evaluation, we found that most compounds of N series exhibited high inhibition to HDAC, some of which had IC50 values close to the magnitude of nanomole. But the antiproliferative activity of them was limited. Compounds of X series showed both high HDAC inhibition and high antiproliferative ability. Compound X3 is a HDAC inhibitor with IC50 value of 70nM. It exhibited high antiproliferative effects not only in hematologic malignancies, such as multiple myeloma, lymphoma and acute myeloid leukemia, but also in solid tumor, such as hepatoma and colon cancer. Besides, X3 showed similar in vivo antitumor ability with SAHA. As a promising lead compound, X3 deserves further research and development.