Stereoselective Synthesis And Antitumor Activity Of Mu Ltichiral Dihydrochromoncyclohexane-spirooxindoles

At present,the incidence of malignant tumors is getting higher and higher,and the drugs for treating malignant tumors are generally toxic and side effect and prone to drug resistance,so it is urgent to find new high-efficiency and low-toxic anti-tumor drugs.Spirooxindole Compounds exist widely in nature and have a variety of biological activities,including antitumor activity.Although this kind of compound has been studied for a long time,due to its great signi ficance in the field of medicinal chemistry,it is still a hot spot in the field of medicinal chemistry,and there is still a lot of research space.Xanthone is a xanthone compound with anti-tumor,anti-fungal,anti-HIV and other activities.Heterocyclic compounds play an important role in the design and discovery of new physiologically active compounds.Two or more skeletons are spliced into a skeleton molecule with potential biological activity,in order to optimize the original skeleton molecule to increase its activity or Reduced toxic and side effects,which is an important method in the design of new drugs.This topic is mainly divided into three parts:(1)Synthesis of dihydrochromone bispiro[oxindole-benzofuranone] compounds.Initially,we studied the reaction of chromone-oxindole synthon with tert-butyl ester substituted 3-methylenebenzofuranone catalyzed by quinine-derived squaramide-tertiary amine Cl.Gratifyingly,the designed inter-/intramolecular Michael cycloaddition reaction indeed afforded the desired product 3a in a 78% yield albeit with 99% ee and >20:1 dr.This preliminary result demonstrated the feasibility of our design.In order to improve the yield,the catalyst and solvent were screened in sequence.It was found that 10 mol % of quinine-derived thiourea-tertiary amine catalyst C2 fully converted chromone-oxindole synthon into the desired product 3a with good control over the stereochemistry(90% yield,99% ee,>20:1 dr).Finally,we asymmetric synthesized 19 dihydrochromone bispiro[oxindole-benzofuranone] compounds(3a-3y,4a-4d)by the bifunctional chromone-oxindole synthon and 3-methylenebenzofuranone.Such compounds bearing five consecutive stereocenters including two spiro quaternary carton centers.The reaction scope generally proved to be broad with respect to a wide variety of electron-rich and-poor reagents to give diversely substituted dihydrochromone bispiro[oxindole-benzofuranone] in 70%-93% yields with 75% to > 99% ee and up to >20:1 dr.(2)Synthesis of dihydrochromone bispiro[benzofuranone-benzofuranone] compounds.Inspired by the success in the chromone-oxindole synthons,considering that bispiro[benzofuranone-benzofuranone] would be medicinally important hybrids for the development of new biological molecules,subsequently,we further designed and synthesized a novel bifunctional chromone-benzofuranone synthon as a 4C synthon and was then subjected to 3-methylenebenzofuranone at room temperature.The reaction proceeded smoothly,affording bispiro[benzofuranone-benzofuranone] 5a in 68% yield with 96% ee,92:8 dr.Finally,we asymmetric synthesized 11 dihydrochromone bispiro[benzofuranone-benzofuranone] compounds(5a-5k)by the bifunctional chromone-benzofuranone synthon and 3-methyleneb enzofuranone.Similarly,Such compounds bearing five consecutive stereocenters including two spiro quaternary carton centers.The reaction scope generally proved to be broad with respect to a wide variety of electron-rich and-poor reagents to give diversely substituted dihydrochromone bispiro[benzofuranone-benzof uranone] in 58%-80% yields with 93% to >99% ee and up to >20:1 dr.Moreover,this is the first example of bifunctional chromone-benzofuranone synthon directed organocatalytic tandem reaction,potentially useful in medicinal chemistry.(3)Evaluate the in vitro antitumor activity of the synthesized compounds.We used cisplatin(CDDP)which the first-line treatment of solid tumor as a positive control,six dihydrochromone bispiro[oxindole-benzofuranone] compounds were extracted for in vitro antitumor activity evaluation.We studied the anti-proliferative activity of compounds 3x,3y,4a~4d on Human chronic myeloid leukemia cell line K562 in vitro.The results showed that compounds 4a,4c and 4d had a certain inhibitory activity on the proliferation of K562,which indicated that the dihydrochromone bispiro[oxindole-benzofuranone] compounds can be used as a lead compound for further study.