Theoretical And Experimental Studies Of Novel Chalcone (LHCs) On The Activities Of Anti-Tumor

Objective:In natural plants, many compounds have anti-tumor activity. We mainly studied the anti-tumor activity of chalcone compounds. A series of chalcone compounds have been produced with the guiding of CADD. To discover the new anti-tumor drugs, the anti-tumor activity and pharmacophore of the compounds were researched.Methods:1. Anti-tumor targets (PTK) were selected as docking receptors. Imatinib, dovitinib, gefitinib, lapatinib, sunitinib, cediarnib, canertinib, erotinib and dasatinib were selected as masculine ligands. Hydrocortisone, captopril, clofibrate, zafirlukast, rosiglitazone, theophyline and aspirin were selected as feminine ligands. We investigated the binding capability between molecules of LHC and receptors by the gliding docking function of computer-aided drug design software Schrodinger8.02. MTT was used to evaluate the preliminary anti-tumor effect of the compounds. Cell growth inhibition rates and IC50were reference to evaluated toxicity for tumor cells. The cell strains we used are human gastric adenocarcinoma cell SGC-7901, human breast carcinoma cell MCF-7, human pancreatic carcinoma cell SW-1990and human lung cancer cell A-549.3. Healthy adult KunMing mice were selected. Human liver carcinoma cells H22suspl. were subcutaneously injected into mice’saxillary fossa. The following day, the mice were randomly divided into five groups (control, Cyclophosphamide, high-dose, middle-dose, low-does). After10days, the tumors in axillary fossa were picked out and weighted. Tumor index number was calculate to evaluate the anti-tumor effect.4. Develop pharmacophore model of software Schrodinger8.0was used to build the pharmacophore model to find the pharmacophore of compounds LHC.Results:1.The docking score and glide energy between ligands and receptors showed:Aurora-a kinase can be nonspecific inhibited by compounds LHC. Ber-ablis specific inhibited by LHC-09and LHC-11. EGFR is nonspecific inhibited by LHC-02, LHC-08, LHC-09, LHC-11. FAK can be nonspecific inhibited by nearly all the compounds LHC. C-met, Raf-2and ROR are nonspecific inhibited by the compounds LHC.2. LHC-01-LHC-06can suppress the proliferation of four tumor strains. LHC-11has the effect to human pancreatic carcinoma cell SW-1990. LHC-12has the effect to human breast carcinoma cell MCF-7and human pancreatic carcinoma cell SW-1990. According to IC50, LHC-02strongly inhibits the proliferation of four tumor strains LHC-03strongly inhibits the proliferation of human breast carcinoma cell MCF-7. LHC-06strongly inhibits the proliferation of human pancreatic carcinoma cell SW-1990and human lung cancer cell A-549.3. Experiment in vivo show LHC-02has toxicity with the high-dose, but no anti-tumor effect with low-dose. Only the middle-dose can suppress the proliferation of tumors.4. Pharmacophore of Compounds LHC include two aromatic rings, oxygen of hydroxy group at2’site and alkoxyl at4’site of A ring, oxygen of acrylketone. These groups are hydrogen bond accepter. Heterocyclic ring at3’site of A ring and chlorine at2’site of B ring are hydrophobic group. Nitrogen at heterocyclic ring is positive charge group.Conclusion:1.Compands LHC can bind to anti-tumor target stablily. CADD is a good guid when studying the new type of medicine.2. The compounds LHC have anti-tumor activity and also toxicity.3. The pharmacophores of compounds LHC include oxygen of hydroxy group, hydrophobic group, et al. These groups make the compands and receptors bind with the effort of electrostatic interaction, hydrogen bond, hydrophobic interaction to show the anti-tumor activity.