Anti-tumor Studies Of Three Small Chemical Molecules

Cancer is a serious threat to human health and has become the second cause of the human deaths all over world.Chemotherapy plays an important role in cancer therapy.Natural products and their derivatives are important sources of antitumor drugs.The discovery of novel antitumor active compounds and their targets and mechanisms are important research contents of antitumor drugs.The gibberellins are a family of tetracyclic diterpenes presented widely in the plant kingdom.Gibberellins are biosynthetically from kaurene Diterpenoid.Many of those compounds possess interesting biological activities.Based on gibberellin,it is of great research value to obtain novel derivatives with higher activity through structural modification.In the second chapter of the thesis,the antitumor activity of novel 35 allogibberic acid derivatives was studied.and it was found that the α,β-unsaturated carbonyl unit is responsible for anti-neoplastic activities,among which compound C45 showed significant cell proliferation inhibitory activity.Further mechinism studies showed that C45 could cause S cell cycle arrest and induce apoptosis.Weel kinase is functionally a tyrosine kinase.As a kind of cell cycle regulatory proteins,Weel kinase is a key molecule in maintaining G2/M cell cycle checkpoint arrest for premitotic DNA repair.Inhibition or downregulation of Weel kinase could trigger the mitotic catastrophe.In the third chapter of the thesis,MTS method was used to evaluate the antitumor activity of a series of chemically synthesized Weel inhibitors in vitro,and it was found that compound B1 could effectively inhibit the proliferation of tumor cells in vitro,and its antitumor mechanism was studied,it was found that compound B1 could induce G2/M cell cycle arrest and apoptosis.Microtubules are cytoskeletal filaments in cells and play an important role in maintaining cell morphology,participating in cell motility,signal transduction and mitotic spindle formation.They are extremely important in the process of mitosis and cell division,which make them an important target for anticancer drugs.In the fourth chapter of the thesis.The effect of ent-kaurane diterpenoid compounds on inhibition of tubulin polymerization was examined using a Tubulin Polymerization Assay Kit.Among them,Oridonin can promote microtubule depolymerization in a dose-dependent manner,and further mechanism studies have shown that it can promote microtubule and spindle depolymerization by binding to tubulin to induce cell cycle G2/M arrest and apoptosis.This study enriched the structure types of the microtubule inhibitors and the anti-tumor mechanism of the ent-kaurane diterpenoid.