Studies On New Type Of Protein Tyrosine Kinase Inhibitors (compounds Of Zht)

Objective:Cancer is a vicious disease threatened to our health, many cancers are close correlated to over-expression and activation of protein tyrosine kinase receptors. Protein tyrosine kinases are proteins which have enzymatic activity. And they are one of the cores of cell signaling conduction. Over-expression and activation of protein tyrosine kinase receptors is common in many cancers. We synthesized series of new protein tyrosine kinase inhibitors based on the structure of flavonoid we had. Preliminary determination is carried out on their anti-cancer effect. Besides, we made research on their mechanism of action by theoretical study.Methods:1. We selected 1XKK,1AGW,1PKG,1Y6A,10EC and 20J9 as docking receptors and lapatinib, dasatinib, imatinib, sunitinib, sorafenib and dovitinib as masculine ligands. We selected zanamivir,linezolid,aspirin,ritonavir and cephalosporins parenteral actinonin as feminine ligands. We investigated the binding capability between molecules of ZHT and protein tyrosine kinase receptors by computer-aided drug design software Gold 3.0.1 and Glide7.5.112.2. We made structural modification on the flavonoid, synthesized target compounds and identified their structures by 1H-NMR and 13C-NMR. 3. MTT was used to evaluate the preliminary anti-cancer effect of the target compounds. And we evaluated their toxicity to tumor cells by cell growth inhibition rates. The cell strains we used are human granulocytic leukemia cell HL-60, human gastric adenocarcinoma cell SGC-7901, human colon carcinoma cell SW-480 and human breast cancer cell MCF-7.Results:1. We designed and synthesized the target compounds ZHT002～ZHT011.2. The docking score and glide energy between masculine ligands and receptors are good. The binding capability between molecules of ZHT and various protein tyrosine kinase receptors had no obvious difference. But it has some binding pattern between them.3. The pharmacological effect showed:Compared with positive control, ZHT009 and ZHT010 exhibited good effect to the four tumor strains which cultured in vitro, the 50% inhibiting concentration is lower than 7.76μg/ml. ZHT010 exhibited best effect to human gastric adenocarcinoma cell SGC-7901, the 50% inhibiting concentration is 0.64μg/ml. The 50% inhibiting concentration of ZHT009 to human granulocytic leukemia cell HL-60, human gastric adenocarcinoma cell SGC-7901, human colon carcinoma cell SW-480 and human breast cancer cell MCF-7 is 3.44,7.16,4.86,7.76μg/ml; the 50% inhibiting concentration of ZHT010 to human granulocytic leukemia cell HL-60, human gastric adenocarcinoma cell SGC-7901, human colon carcinoma cell SW-480 and human breast cancer cell MCF-7 is 1.58,0.64,2.47,5.22μg/ml; the 50% inhibiting concentration of ZHT001, ZHT005, ZHT007 and ZHT011 to human granulocytic leukemia cell HL-60 are 27.01, 58.55,16.59,21.36μg/ml; ZHT002, ZHT004 and ZHT008 showed no activity to this cell strain. Other ZHT compounds had no activity to human gastric adenocarcinoma cell SGC-7901, human colon carcinoma cell SW-480, human breast cancer cell MCF-7 except ZHT009 and ZHT010.Conclusions:1. The compounds of flavonoids we designed based on protein tyrosine kinase showed obvious anti-cancer activity, and our theoretical studies are feasible.2. The activity of the synthetic compounds is coincident with the target structures. It showed that the compounds maybe multi-target protein tyrosine kinase inhibitors.3. The structures of compounds of ZHT were identified correct by 1H-NMR and 13C-NMR.4. ZHT009 and ZHT010 showed powerful lethal effect to the four tumor strains; ZHT001, ZHT005, ZHT007and ZHT011 have activity to human granulocytic leukemia cell HL-60 to some extent.