Asymmetric Synthesis And Anti-tumor Activity Of Dihydrochromone And Cyclopentane Spiro Compounds

Cancer is a serious threat to human health.It has become not only the second largest disease after cardiovascular and cerebrovascular diseases in China,but also one of the important causes of disease and death in the world.As the world's population increases and the population ages,the global cancer burden is expected to continue to increase.The American Cancer Research Association states that the total number of cancer patients worldwide is expected to reach 27.5 million and will cause16.3 million deaths by 2040.At present,drug resistance is one of the main causes of death in cancer patients.The important ways to overcome drug resistance are gene therapy,immuno therapy,antibody therapy,development of tumor drug resistance reversal agents,and development of small molecule compounds for drug resistance tumors.However,it is an important way to overcome drug resistance in tumors that the development of small molecular compounds that are resistant to drug-resistant tumors.Therefore,it is important to develop a new generation of antitumor drugs with small toxic and side effects.Studies have shown that compounds containing a spiro-epoxidized indole skeleton in natural products have a variety of pharmacological activities.For example,they are anticancer,antiinflammatory,antibacterial,antiviral,antimalarial and inhibition of cholinesterase.But the antitumor activity is particularly prominent in such skeleton structures.For example,diindolepyridylthiazolidine can inhibit the proliferation of A549 cells by reducing the phosphorylation levels of Akt/m TOR and inhibiting the expression of cyclin.It is A cell cycle blocker that blocks tumor cells in the G1 phase by inhibiting cyclin-dependent kinase 2?CDK2?that the new anti-resistant tumor drug3-substituted aryl indole?PHII 7?.In the first part of this thesis,based on the principle of skeleton migration and splicing in drug design,the dihydrochromogenone skeleton and the indoloquinone skeleton are spliced to synthesize a new type of dihydrochromogenone and cyclopentane compounds,which can be biologically active Screening provides the material basis.For the first time,quinine thiourea was designed as a chiral catalyst to catalyze the asymmetric Michael/Michael[3+2]cycloaddition reaction between nitrostyrene and 3-substituted indole oxides.We obtained a high Yield??80%yield?,diastereoselectivity?>20:1 dr?and enantioselectivity?>99%ee?.The absolute molecular configuration is identified by single crystal diffraction.The molecular structure is identified by nuclear magnetic resonance.The relative molecular weights is identified by high resolution mass spectrometry.We have synthesized 23compounds.Then we used the MTT method to study the antitumor activity of the 23compounds synthesized in vitro.The IC₅₀of compound de-Boc 3j on K562 tumor cells is 32.1?mol/L.The IC₅₀of compound de-Boc 3p on K562 tumor cells is 40.8?mol/L.The IC₅₀of compound de-Boc 3r on K562 tumor cells is 36.1?mol/L.The IC₅₀of compound de-Boc 3v on K562 tumor cells is 37.7?mol/L.While the IC₅₀of positive control cisplatin on K562 tumor cells is 23.2?mol/L.In the second part of this thesis,based on the principle of skeleton migration and splicing in drug design,the indoloquinone skeleton chromone compounds and nitroisoxazole olefins were spliced to synthesize new dihydrochromogen and cyclopentane compounds,which can provide material basis for biological activity screening.For the first time,we designed TBAB and K₂CO₃as catalysts to catalyze the[3+2]cycloaddition reaction of nitroisoxazole and 3-substituted indole oxide.We obtained a high yield??75%yield?.The relative molecular configuration is identified by single crystal diffraction.The molecular structure is identified by nuclear magnetic resonance.The relative molecular weights is identified by mass spectrometry.We have synthesized 20 compounds.