Synthesis And Bioactivity Evaluation Of Spiro[Hexahydrocyclopenta[b] Chromanone-Oxindole]s

Nowadays,with the increasing frequency of malignant tumors,human life and health are seriously threatened.For this reason,it is urgent to find a way to treat malignant tumors.Based on the current severe background,the research and development of anti-tumor drugs will inevitably become a focal subject that humans need to overcome.The current drugs for the treatment of malignant tumors have not yet reached the requirements of high efficiency and low toxicity,and need to be continuously improved and perfected.Natural products have a prominent position in the field of exploring biologically active compounds.Because of their different core frameworks and a large number of types,they have laid a foundation for the design and development of new drugs.The complexity and diversity of its molecules provide a basis for the discovery of new drugs and the research of new synthetic and semi-synthetic derivatives.The huge chemical diversity provides inspiration for synthetic chemistry and medicinal chemistry.Many lead drugs have carried out clinical pharmacological research,which has great research potential and good development prospects in the treatment of various diseases.Studies have shown that many natural compounds with unique core frameworks in nature have excellent pharmacological activities.For example,spiro indolinone is more common in a large number of natural products and important drug molecules.Because of its better biological activity.In the past few years,researchers have made considerable efforts to synthesize compounds with a spirocyclic indolinone skeleton.Among them,diketopiperazine alkaloids,a compound with a spirocyclic indolinone core skeleton,has good pharmacological activity;The ketone core skeleton is an important structural element,which is widely present in synthetic and natural products.This class of compounds has excellent biological and pharmacological activities.In addition,the ketoester group is also an important pharmacophore group.These special framework structures provide a direction for the exploration of anti-tumor drugs.Several active frameworks have been modified and spliced to further enhance their biological activities,and new ones with higher effectiveness and affinity than the parent drug have been obtained.The new compound has the characteristics of optimizing pharmacodynamics and pharmacokinetics.In addition,strict control of the configuration of drug molecules can effectively reduce the toxic and side effects of chiral drugs,so asymmetric synthesis of drugs is particularly important.In this thesis,asymmetric synthesis reaction is used to construct a target compound that integrates spirocyclic cyclohexane indolinone,ketone ester,xanthone and other advantageous skeletons in order to obtain drug molecules with higher pharmacological activity.The structural compound can be realized by intermolecular and intramolecular Michael/Michael cycloaddition.It can fill the existing lead drug depository,which is of great significance to the design and research and development of new drugs.The constructed compounds are screened for anti-tumor activity in vitro,and the structure skeleton of the lead compound with better activity is sought.Open up new fields of inquiry for new drug design and drug research.This topic is mainly divided into two parts:（1）Synthesis of hexahydroxanthones spliced spiral oxindoles skeleton and ketone ester group compoundsFirst,the reaction of bifunctional chromone-oxindoles synthon andβ,γ-un-saturatedα-ketoester under the catalysis of quinine thiourea chiral catalyst was studied.The hexahydroxanthone skeleton compound containing this type of spirocyclic indole was synthesized for the first time.The results show that the design ideas using the above-mentioned synthon and the intermolecular/intramolecular Michael cycloaddition reaction mechanism are correct and feasible.It can realize the highly diastereomeric and enantioselective synthesis of a series of biologically related spirocyclic hexaxanthones with a series of quaternary ammonium and quaternary stereoisomeric centers,and has two priority motifs.combination.The expected product 3a was obtained.The yield was 63%,and the ee value was 95%.In addition,the use ofβandγ-unsaturatedα-ketoesters as building blocks is different from enone substrates with reversible Michael reactions such as chalcone and benzophenone,which further expands its scope of application.Finally,fromβ,γ-unsaturatedα-ketoester and the bifunctional chromone-oxyindole synthon,a hexahydroxanthone spliced spiroepoxy indole skeleton with five consecutive chiral centers was synthesized asymmetrically.23 ketone ester group compounds（3a-3w）.The substrates of the reaction have good compatibility with various electron-withdrawing substituents and electron-donating substituents,and the range of substrates is relatively wide.It has good yield（56%-76%）and good diastereoselectivity（dr>20:1）,as well as good enantioselectivity（ee:93%-99%）.The ee value of the compound is determined by HPLC;the dr value is jointly determined by HPLC,¹³C NMR,and ¹H NMR;the structure of the compound is jointly determined by ¹³C NMR,¹H NMR,and MS-ESI.（2）The anti-tumor activity of the synthesized hexahydroxanthone spliced spiral oxindoles skeleton and ketone ester group compound was evaluated in vitro.The 3 hexahydroxanthones spliced the spiro-epoxidized indole skeleton and the ketone ester group compounds 3s,3u,3i through the MTT method and selected the first-line anticancer drug cisplatin（cis-dichlorodiammine platinum）For the control test,the IC₅₀of compound 3s to K562 was 44.5μmol/L;the IC₅₀of compound 3u to K562 was 53.1μmol/L;the IC₅₀of compound 3i to K562 was 76.5μmol/L;the experimental results can draw conclusions:The three hexahydroxanthones spliced spiro-epoxidized indole skeleton and ketone ester group compounds 3s,3u,3i have a certain inhibitory effect on the human chronic myeloid leukemia cell line K562.Therefore,the spiro-epoxidized indole skeleton and ketone ester group compounds of hexahydroxanthone can be used as lead compounds for further study.