A Study On The Synthesis And Antitumor Activities Of Chromanone-fused Pyrrolidinyl-spirooxindole Compounds

According to the principle of active scaffold hopping and splicing in drug design,it has become an important pathway that splicing two or more frameworks with pharmacological activity into a potential active molecule for new drug discovery.The chromanone skeleton which are considered‘privileged structures'are often encountered in nature and among pharmacologically active compounds like elaeocarpine,diaportheone B,tephrosin cremastranone,deguelin and so on.However,the efficient routes to access this type of heterocycle-fused chromanones are still limited,mainly ascribed to the inherent inertness of the chromones as the starting materials.The diversity-oriented construction of heterocycle-fused chromanone scaffolds are highly desirable and might facilitate the search for new bioactive entities.3,3'-pyrrolidinyl-spirooxindoles have represented a prominent structural motif encountered in a large number of natural products,such as spirotryprostatins A,pteropodine and pharmacologically active compound MI-888.Which has a wide range of biological activities,especially anticancer activity has attracted much attention of researchers.In this context,we designed a series of 3,3'-pyrrolidinyl-dispirooxindole compounds with the bioactive skeleton chromanone,and analyzed their anti-tumor activity in vitro,which will help in search for new potential lead compounds.The first chapter:using a decarboxylative 1,3-dipolar cycloaddition approach of chromone-3-carboxylic acid with azomethine ylide?generated in situ from isatins and proline,thioproline or sarcosine?efficiently struct chromanone-based 3,3'-pyrrolidinyl spirooxindole compounds.This innovative method was that,through a carboxylic acid-activation and then decarboxylation strategy,activate little reactive chromone.A wide variety of products with three or four contiguous stereocenters including a spiro quaternary stereocenter were smoothly prepared in up to 90%yield and 20:1 diastereomeric ratio with high efficiency.The second chapter:The direct use of ammonium hydroxide in amination for the synthesis of primary amines is considered to be one of the major challenges in synthetic organic chemistry.Herein,the first example of catalyst-free direct amination of 3-halooxindoles with ammonium hydroxide to synthesize N-unprotected3-tetrasubstituted aminooxindoles in high yields?up to 91%yield?is described.An enhancement of the reaction rate on using water was observed under mild conditions.Such an approach is not only protection/deprotection-free,but also more practical and cost-effective.Moreover,this method could expand the library of 3-tetrasubstituted aminooxindole building blocks for the further synthesis of AG-041R,GHSR antagonists and a charteline unit,opening up a new synthetic pathway in the chemistry of 3-aminooxindoles.The third chapter:These synthesized compounds were tested anti-tumor activity in vitro with the method of MTT.And we used the clinical anticancer drug cisplatin as positive control to test its effect.Some chromanone-fused pyrrolidinyl-spirooxindoles exhibited considerable cyotoxicities,The IC₅₀?K 562?of the compounds 1c,2ac,2bb,2bf,2bg,2bh were 42.78?M,35.04?M,41.57?M,47.53?M,21.10?M,35.28?M respectively,and reached the same order of magnitude as Cisplatin(IC₅₀=23.05?M).the remaining compounds showed no good activity for PC-3 cells and A549 cells.