Studies Of Novel Aurora Kinases Inhibitors On The Activities Of Anti-tumor

Object i ve:We mainly looked for the anti-tumor activity of inhibitors of Aurora kinases (TZA series). A series of compounds which basic structure is pyrazoloquinazolines have been produced with the guiding of CADD. To discover the new anti-tumor lead compounds, the anti-tumor activity were researched.Methods:1. The crystal structures of Aurora kinases and other serine/threonine kinases were selected as docking receptors. Hesperadin, ZM447439, MK0457, MLN8054, PHA-739358, AZD1152and its active metabolic product named AZD1152-HQPA were selected as masculine ligands. Hydrocortisone, captopril, clofibrate and aspirin were selected as feminine ligands. We investigated the specific binding.capability between molecules of TZA series and receptors and inhibiting Aurora A and B of TZA series by the glide docking module of CADD software Schrodinger9.0.2. MTT was used to evaluated the preliminary anti-tumor effect of the compounds. Cell growth inhibition rates and IC50were referenced to evaluate toxicity for tumor cells. The cell strains we used are A549cells (carcinomic human alveolar basal epithelial cells),SW1990cells (human pancreatic cancer cells), COLO205cells (human colon adenocarcinoma cells), HUVEC (human umbilical vein endothelial cells). The morphocytology of A549cells and LoVo cells (colon cancer cells) was observed by HE stain.3. Healthy adult KunMing mice were selected. S180tumor suspension was subcutaneously injected into mice’s subaxile fossa. The following day, the mice were randomly divided into14groups (control, CTX,2doses per sample). Take these samples every other day. After4times, tumors were picked out and weighted. The inhibition rate on S180tumor cells was calculated to evaluate the anti-tumor effects and toxicities.Results: 1. The grading results showed:Aurora A can be moderately bound with TZA8002-TZA8006. It can be moderate binding ability between TZA8005and Aurora B. As well as increasing the steric hindrance of lipophilic pocket of compounds, cyclic amine side chain of Quinazoline C-7will be in favor of increasing the binding ability between TZA series and Aurora kinase. TZA series may be multitargeted moleculars.2. TZA8001can inhibit the proliferation of A549cells at10μg/mL concentration. At the same concentration, TZA8001-TZA8007suppress the proliferation of COLO205cells. TZA8001-TZA8006suppress the proliferation of SW1990cells, inhibition of TZA8004is the strongest. IC50values showed TZA8001, TZA8003, TZA8004strongly inhibit the proliferation of COLO205cells. TZA8002, TZA8005, TZA8006strongly inhibit the proliferation of SW1990. At the higher concentration, TZA8001-TZA8006have toxicity with HUVEC in vitro. The morphocytology of A549and LoVo cells has exhibited an oncosis. This condition of LoVo cells is more obvious. Inhibition of TZA8001is stronger than TZA8004.3. Results in vivo show TZA8001-TZA8006have anti-tumor effect with2doses. TZA8001has a little toxicity.Conelusion:Based on docking methods, we designed Aurora kinases inhibitors (molecules of TZA series). The molecules can bind to Aurora kinases specifically. We evaluated the anti-tumor activities of the series of compounds we synthesised in vivo and in vitro. Part of them have obvious anti-tumor activities. These results show the pathway from theory to experiment was effective.