Design, Synthesis And Anticancer Activity Study Of Cinnamamide Derivatives As Histone Deacetylases Inhibitors

Tumor has become the second killer of humen health following the heart disease. It is caused by diverse reasons including environmental pollution, chemical pollution, radiation, microorganism, hereditary capacity, unbalance of internal secretion. Because of the development of science technology and the damage of environment, humen now are likely to be hurt by such cancerogen, and the rate of tumor is increasing year by year. Due to the characters of diverse pathogenesis and recurrence of cancer, cure of cancer has become the biggest puzzle for humen. Now methods for cancer are mainly about operation, radiate, chemistry and preventive medicine. As a chemist, we mainly design and synthesize new compounds on the base of relevant cancer target, and then value their antitumor activities. HDAC which is regared as intracellular metalloprotease has been regarded as a new target and hot point for cancer treatment. HDAC plays an important role for gene expression and posttranscriptional modification. In tumor cells overexpression of HDACS increases hyperdeacetylation of histone which causes hypercombination of histone and DNA, at last transcription is suppressed. So inhibition of HDAC can inhibit the proliferation of tumor and cause apoptosis.With the development of computer science and technology, together with its combination with drug screening and design, the rationality of drug design and the efficiency of drug synthesis have been greatly improved. This dissertation is mainly for the design of small molecular compounds, on the basis of existing work in our laboratory through the study of the biological activity evaluation of cinnamide compounds, with the aid of computer aided drug design software, the study of the structure-activity relationship, and chemical structure of clinical compound LBH-589.,We used L-Trp (L-tryptophan) as raw material to design a series of cinnamide-based hydroxamic acids as histone acetylation enzyme inhibitor., We introduced different aromatic acid groups on the amino N of L-Trp to examine the structure-activity relationship of the synthetic compounds, such as hydrophobic effect, electrical effect and three-dimensional effect..In this dissertation,24 newly-synthesized compounds were reported. The structures have been confirmed by mass spectrum (MS) and 1H nuclear magnetic resonance (1H-NMR).At last, activities of these compounds were assessed at molecular level and cellular level. Cinnamamide derivatives were firstly assessed using Hela cell nuclear extract and then Hela、U266 and U937 tumor cell lines. The work above provides important information for future development of HDACi.