Synthesis And Antitumor Activity Of Derivatives Of Isatin And Tryptanthrin

Leukemia is a type of malignant tumor that threatens the health of human today.The incidence of chronic myeloid leukemia in China is about 1-2/100,000,which ranks third of leukemia in China.Currently,the most commonly used leukemia therapeutics is the first-generation tyrosine kinase inhibitor such as imatinib and the second-generation tyrosine kinase inhibitor such as Nilotinib et al.The research and development of leukemia therapeutic agents have been a hot spot in the field of medical research all the time.Indirubin is an anti-leukemia active ingredient extracted from the traditional Chinese medicine preparation"Danggui Longhui Wan",and is also an effective active ingredient in the traditional Chinese medicine Qindai.Previous studies in our laboratory have found a one-step coupling of reduced isatin to synthesis indirubin.The 3-position carbonyl of isatin is reduced and condensed to another isatin to form an intermediate.This intermediate is oxidized by oxygen in the air to obtain indirubin.Inspired by this,we believe that isatin can be reacted with other compounds containing a carbonyl structure to obtain isatin derivatives whose structure is partially similar to indirubin.The condensation of the amide bond of isatin and the activated portion of the isatoic anhydride to obtain tryptanthrin is the most commonly used method for the synthesis of tryptanthrin.The structure of the isatin derivatives obtained from the reaction of isatin and carbonyl-containing compound retains the amide bond of isatin,so we consider that these isatin derivatives can condensed with the activated portion of the isatoic anhydride to obtain tryptanthrin derivatives.In this thesis,the aldehydes were added to the process of the reduction coupling of isatin,based on the reaction of one-step coupling reduction of isatin to synthesize indirubin derivatives.Among the eighteen explored aldehydes,eight of them were obtained the products.The reaction gave the aldehyde derivatives of isatin,one of them was not reported in the literature.According to the reaction of the condensation of isatin with isatoic anhydride to form tryptanthrin,the isatin derivatives obtained in above were condensed with isatoic anhydride,and four tryptanthrin derivatives were obtained.This new method for the synthesis of isatin and tryptanthrin derivatives is simple and convenient,the reaction conditions are mild,and the raw materials are cheap and easy to obtain.Twelve kinds of isatin and tryptanthrin derivatives have been obtained.This suggests that our approach to the synthesis of isatin and tryptophan derivatives is feasible.Antitumor activity experiments of the above 13 compounds were carried out using human lung cancer cell line A549,human colon cancer cell line HCT116,human chronic myeloid leukemia cell line K562 and human hepatoma cell line HepG2.The results showed that the inhibitory effect of HCT116 was better than that of the other three cell lines.Among them,（E）-3-（3-hydroxy-4-methoxybenzylidene）indolin-2-one（A₃）,（E）-6-（3-hydroxy-4-methoxybenzylidene）indolo[2,1-b]quinazolin-12（6H）-one（B₂）,（E）-6-（4-（benzyloxy）benzylidene）indolo[2,1-b]quinazolin-12（6H）-one（B₃）and（E）-6-（2,4,6-trimethylbenzylidene）indolo[2,1-b]quinazolin-12（6H）-one（B₄）had stronger inhibitory effects on HCT116,and their IC₅₀0 values were 5.81μmol/L,1.88μmol/L,0.07μmol/L,4.62μmol/L,respectively.（E）-3-benzylideneindolin-2-one（A₁）had better inhibition of A549,IC₅₀0 value was 2.83μmol/L.