Preparation Of Nitrogen-substituted 3-Oxo-6-substituted Tetrahydroquinoxaline Derivatives And Their Biological Activity

Microtubules are an important component of the cytoskeleton structure,which is closely related to the synthesis and movement of intracellular substances and is involved in the localization and movement of chromosomes.It plays a key role in mitosis.The spindle is composed of the early stages of mitosis,and its "accessory" is microtubules and microtubule subunits in the cytoplasm.At the end of the mitosis,the change between the microtubule and the spindle is just the opposite of the previous process.The mutual transformation between the spindle and the microtubule is important in the cell cycle.If some of the conditions change and make its dynamic balance changes or even damage,cell division cycle arrest induced apoptosis of the cell.Combretastatin A4(CA-4)is a small molecule natural product isolated from South African willow,which can inhibit the polymerization of tubulin and has good antitumor activity.However,its poor water solubility and structural instability limit its clinical application.The current report on the construction transformation of Combretastatin is mainly included:(1)The introduction of phosphoric acid,amino acid and other structures to improve its water solubility.(2)With sulfonamide,carbonyl,five membered aromatic heterocyclic ring to replace the double bond to solve the problem of its double bond instability in the body.In this paper,18 target compounds were designed and synthesized on the basis of CA-4 skeleton structure.Their structures were confirmed by 1H NMR,1 C NMR and ESI-MS,and their stability and antitumor activity were studied.The main contents of the study include:1.In this paper,a series of novel compounds with nitrogen-substituted 3-oxo-6-substituted tetrahydroquinoxalines were designed and 18 target compounds were prepared by suitable synthetic routes;2.In this paper,the anti-tumor activity of these compounds was studied,including the inhibition of proliferation of tumor cells(MTT assay),inhibition of tubulin polymerization and cell cycle arrest.The inhibitory effects of tubulin polymerization on 5c,10c and 10d were studied,and the cell cycle was studied on 10d.The results showed that compounds 5c,10c and 10d had a significant inhibitory effect on tubulin polymerization at 20 μM,and the half inhibitory concentration(IC50)of the inhibitor 10d on the inhibition of tubulin polymerization was 3.9 μM,and at a concentration of 0.15 μM Cells were apparently blocked in G2/M phase.