Preparation And Anti-leukemic Cells MV4-11 Activities Of Histone Methyltransferase Inhibitor FK106

Leukemia is a malignant disease that is suppressed in normal hematopoiesis.Its hematopoietic stem cells lose their differentiation ability.It shows malignant clonal proliferation and accumulation in bone marrow and other hematopoietic tissues,and invade the liver,spleen and lymph nodes.Eventually,they infiltrate and destroy all tissues and organs.According to statistics,Leukemia accounts for about 3%of the total tumor incidence.The incidence of pediatric malignancies is 35%,ranking the first.It is the most common malignancy among children and youth.With the deterioration of human living environment,the incidence of leukemia is also increasing.Histone methyltransferase is involved in histone methylation.It plays an important role in the self-renewal and maintenance of hematopoietic stem cells and is an important target for the treatment of leukemia.Histone methyltransferase inhibitors have become an important direction in the treatment of new leukemia drugs.In this study,the synthesis and quality of histone methyltransferase inhibitor FK106 and the effect of anti leukemia cell line MV4-11 were studied.The results of the study are as follows:（1）The best synthetic preparation method of the new compound FK106 was screened and the FK106 monomer was obtained.FK106 was identified as the target compound by UV,IR,MS,¹HNMR,and ¹³CNMR.The retrieval found that FK106 was a new compound named N¹,N³-bis（4-iodobenzyl）propane-1,3-diamine.（2）Through the study of the physicochemical properties of FK106.FK106 is a light yellow oil.At the temperature of 25?2℃,FK106 is slightly dissoluble in water,DMSO and dissolved in methanol and ethanol,difficult to dissolve in ethyl acetate.At the temperature of 20℃,FK106 refractive index range is from 1.546 to 1.551.The LgP of FK106 is about 1.2.The fat solubility and water solubility are moderate,and the permeability of biofilm is better.（3）A GC method for FK106 residual solvents has been established,and the method has been investigated by method.The results show that the method is specific,precise and accurate.In the three batch of FK106 samples,methanol and ethanol and ethyl acetate were not detected in the 20170302 batche and the 20170301 batche.Only 20170201batches of ethyl acetate were detected,and the residues were less than 0.5%,which was in line with national regulations.（4）A method for the detection of FK106 related substances by HPLC chromatography was established.The methodological investigation is carried out.,the method is special,accurate and accurate.Confirmation of the related substances contained in FK106 of methanol and formaldehyde on iodobenzene iodobenzene,content were 0.098⁰.114%and 0.108⁰.140%.（5）Two methods for the determination of FK106 content have been established:Non-aqueous titration and HPLC.The methodological investigation is carried out.,the method is special,accurate and accurate.The average content of the two methods for the determination of three batch of FK106 samples was about 99.51%and 99.53%respectively.According to statistical analysis,there is no significant difference between the two methods,which can be used as a method for the determination of FK106 content.The general impurities,such as chloride,sulphate,burning residue,heavy metal and dry weight loss,were examined.（6）The in vitro activity of FK106 to leukemia cell line MV4-11 was studied by CCK-8 and Annexin V-FITC/PI.Found FK106 on leukemia cell line MV4-11 IC₅₀ is 0.391mol/L,significantly lower than the positive control drug ARA-C 28.094 mol/L.The apoptosis rate of MV4-11 after 48 h was significantly higher than that of ARA-C as a positive control drug,and most of it was in the early stage of apoptosis.