Synthesis And Biological Activity Of 1,3-disubstituted Indolinones

With an important nitrogen heterocyclic structure,2,3-dioxindoline?isatin?is widely present in natural compounds and drug molecules.?t is found that the compounds with this structure exhibits a broad range of biological activities,such as anti-inflammatory,antibacterial,antivirus,anti-hypertension,anti-tumor activity.The1,3,4-thiadiazol,thioether and amide are common bioactivity fragments in both medicinal chemistry and natural compounds.which are widely used for the design of drug molecules for their excellent antibacterial,antivirus,insecticide,anti-inflammation and anti-tumor activity.Herein,with 2,3-dioxindoline as a lead compound,forty new 1,3-disubstituted indol-one derivatives were designed and synthesized by introducing thiadiazole thioether amide or amide into the indolone molecule,according to the principle of active splicing.The structure of target compounds was confirmed by ¹H NMR,¹³C NMR,HR-MS?ES??and X-ray.The MTT assay was used to determine the ?nhibition against cancer cell lines of the target compounds against human human liver cancer cells HepG2,metastatic pancreatic cancer cells AsPc-1 and cervical cancer cells Hela.Bioassay result showed that the compounds of series ? and ? exhibited remarkable inhibition activity against tumor cell.The inhibitory rates?v.s Hela cells?of compounds ?-3,?-11,?-13 and ?-14 were 73.97±6.92%,71.79±7.27%,76.71±5.18%and83.31±2.97%,respectively,at a concentration of 50?M.Further studies showed that the ?C₅₀ values of compound?-3 and?-14 were 15.40±0.16 and 14.91±0.21?M,respectively,which are better than that of gefitinib?16.63±0.25?M?,but poor than that of HepG2 cells.At the same time,compounds?-1,?-7,?-14,?-17,?-19,?-20,?-22 and?-23 exhibited remarkable inhibition against HepG2,AsPc-1 and Hela cell lines.Among them,the ?C₅₀ values of the compounds?-14 and?-19 against the above three types of cells were 11.47±0.01,2.43±0.05,1.91±0.06?M,and 14.32±0.01,1.61±0.04,2.77±0.05?M,respectively.which was significantly superior to the Gefitinib?16.41±0.05,5.19±0.02,7.89±0.05?M,respectively?.Finally,the crystal structure of compound ?-14 was confirmed by single-crystal X-ray diffraction and the result showed that compound ?-14 was in the form of monoclinic.The space group was P21/c,the unit cell parameter a=8.368?6??,b=12.160?9??,c=30.60?2??,?=90.038?19?o,?=90.09?9?o,?=105.83?2?o,the volume of the single crystal package was 2996?4??³,the crystal density was 1.179 g/cm³,and each crystal was made up of four compound ?-14 molecules.