Study On Asymmetric Synthesis Of Pyrazolinone Spirobenzofuranones And Their Antitumor Activity

Cancer has attracted much attention and research as a global disease,because the morbidity of cancer has always been high.Therefore,in the research of cancer drugs,it is increasingly urgent to find drugs with high efficiency and low toxicity.In the past research,starting from natural products,the basic synthetic skeleton of a drug or the basic modification of a drug’s privilege nucleus has been receiving more and more attention.The right-handed compound（R-configuration）of the"reaction stop（thalidomide）incident"that occurred in the West in the early 1960s has the ability to inhibit pregnancy response and sedation,while the left-handed compound（S-configuration）has It is teratogenic,which makes people’s molecular structure and pharmacological research of their optically active bodies more and more accurate,so that the asymmetric synthesis of compounds is becoming more and more important in the synthesis of small molecules.The first part is the first synthesizer of chromone-pyrazolone,which is a bifunctional synth.The synthesis of chromone-pyrazolone and 3-enoxyindole has both spiropyrazolone and spiro-epoxydine 30 compounds（3a-3d’）of hexahydroxanthone skeleton of indole,among which,after screening in the previous two unsubstituted template reactions,the yield was 69%-87%under the catalysis of quinuclidinium thiourea.Enantioselectivity is up to 20:1（dr up to 20:1）,enantioselectivity is as high as 99%（ee up to 99%）;chromone-pyrazolinone synthon and 3-enebenzofuranone Eight compounds（5a-5h）with hexahydroxanthone skeletons of spiropyrazolone and spirobenzofuranone.The same optimal reaction conditions as above were selected under the catalysis of quinuclidinium thiourea.The yield is 55%-87%,the diastereoselectivity is up to 20:1（dr up to 20:1）,and the enantioselectivity is as high as 99%（ee up to 99%）.The compound structure was confirmed by ¹H NMR,¹³C NMR,and MS-ESI.The dr value of the compound was determined by ¹H NMR,¹³C NMR,and HPLC,and the ee value was determined by HPLC.The second part of the work is to evaluate the antitumor activity of the synthesized 38 compounds in vitro.The MTT method was used with cisplatin,a commonly used anticancer drug as a positive control,to synthesize 38hexahydroxanthone compounds containing spiropyrazolinone,spiroepoxidized indole,and spirobenzofuranone.The compounds were subjected to antitumor activity studies to investigate the effects of these compounds on the human chronic myeloid leukemia cell line K562.Among them,the compound of 3d、3h and 5g、5h on the half-inhibition concentration of K562 cells were obtained by SPSS software（version19）analysis.The IC₅₀ of compound 3d on K562 tumor cells was 51.09μmol/L;the IC₅₀ of compound 3h on K562 tumor cells was 45.17μmol/L;the IC₅₀ of compound5g on K562 tumor cells was 51.21μmol/L;the IC₅₀ of compound 5h on K562 tumor cells The IC₅₀ of the positive control cisplatin on K562 tumor cells was 20.57μmol/L.Compared with 3d、3h、5g、5h and cisplatin,the inhibitory effects of the other compounds on K562 tumor cells were reduced.