Histone Deacetylase Inhibitors Of Polyoxometalates: Screening And Anti-Tumor Activity

Polyoxometallates (POMs) as enormous structural variety and highly reconcilable in molecular size, surface electric charge distributing, redox potential, acidity, deliquescent and thermodynamic stability, driven by the manifold applications in areas as diverse as materials science, medicine, magnetic, and catalysts. Currently, the research on POMs medicinal chemistry is in one of the highlights in this field. Tumour is one of the serious sicknesses that menace human health. Histone deacetylase inhibitors (HDACi) which are chemicals that restrain the function of histone deacetylase (HDACs) play important roles in diverse cellular functions such as chromatin structure remodeling, gene silencing, cell proliferation, apoptosis and cellular signal transduction.It's the first paper about screening HDACis by using POMs compounds. We have screened five species of effective compounds as histone deacetylase inhibitors (HDACi) from nearly 400 kinds of POMs compounds.The five species of POMs compounds as follow:1. the sandwich type of germanotungstate complexes PA-304 PA-312 PA-313 PA-315 PA-317;2. tri-organic-tin-subsititude germanotungstate compound PA-320;3. transition metals bonded di-Ti-substituted Keggin type of tungstophosphate complexes PA-324 PA-331 PA-332 PA-330;4. super molecular complexes compose of clinical drugs and Anderson type of polyanions PA-301 PA-303;5. Ti-containing tri-polymerize Keggin germanotungstate compound PA-334. PA-320 is selected of representation compound for validating the basic anti-tumour activity.Green fluorescent protein reporter gene photograph shows that PA-320 could enhance the pZS-p21-GFP fluorescent, which is more strengthening than that of TSA. It's approved that PA-320 could stimulate the expression of p21 gene, intuitionisticly. The result of PCR(RT-PCR) approved that the PA-320 controled cell line of different concentraion,in which the expression of p21WAF1/CIP1 gene promoter is the same with that of BUA. It's approved that PA-320 could stimulate the expression of p21 gene.The result of instantaneous integrated HDAC1-7 approved that p21WAF1/CIP1 gene promoter was inhibited most remarkably by HDAC1. Instantaneous integrated HDAC1 controled by PA-320, the activity of p21WAF1/CIP1 gene promoter was increased notablely. The MTT result of PA-320 approved that IC50 values of Hela,LNCaP,293T and SW620 cell line are 38.8679μg/ml,45.1477μg/ml,44.4783μg/ml and 9.2771μg/ml, respectively. It shows that PA-320 could inhibit SW620 cell line in relative low concentration(< 10μg/ml), the inhibiting concentration for Hela,LNCaP, and 293T cell lines are in the ranges of 35-45μg/ml. Compared to the previously reported (> 100μg/ml), PA-320 controled cell line is in low inhibiting concentration.