Design, Synthesis And Evaluation Of Small Molecmle Drugs Against Chronic Myelogenous Leukemia

Chronic myelogenous leukemia?CML?is a disease defined as disordered clonal hematopoietic stem cell and myeloproliferation,which characterized by the Philadelphia chromosome?Ph?.The occurrence and development of CML is critically related to Bcr-Abl tyrosine kinase.At present,the therapeutic targeted drugs of CML are Bcr-Abl tyrosine kinase inhibitor?Bcr-Abl TKI?,but owing to the point mutation of Bcr-Abl gene and P-loop mutation,drug resistance has appeared.The emergence of it has prompted researchers to seek new CML drugs that highly effective,and low-toxic.This paper is based on the results of the structure-activity relationship study of the listed Bcr-Abl TKI,combined with the previous research basis of the group,by utilize the methods of bioelectron isostere and active structure flattening,the pyrimidine nucleus of Imatinib was replaced by the thiazole skeleton of Dasatinib.Meanwhile,we retained the benzamide pharmacophore group,and design a series of thiazole amino-benzamide derivatives.It is expected to obtain small molec?lar drugs that can overcome the drug resistance problems caused by Imatinib and T315I mutations.In order to prove whether our design hypothesis was established or not,we made the following efforts.First,we performed the molecularly docked simulation of the designed compound with Abl and Abl^T315I315I kinase by SYBYL-X2.0,and the fitting score was given.Molecular simulation results show that this series of compounds have strong effect with Abl and Abl^T315I,and the strength of some compounds with Abl and Abl^T315I are higher than that of Imatinib,which indicates that the design can theoretically overcome resistance caused by mutation of Imatinib and T315I.The key intermediate 3-carboxyphenylthiourea is formed by3-aminobenzoic acid and thiocyanate and benzoyl chloride in acetone as solvent.The 3-carboxyphenylthiourea and the bromoarylalkylketone are subjected to a cyclization reaction,an N-acylation reaction and a hydrolysis reactionto give the target compound.The structures of the synthesized compounds were confirmed by analytical methods such as ¹H NMR,APCI-MS,Elemental analysis and IR.In vitro Abl and Abl^T315I kinase activity studies were performed on the synthesized target compounds using a microplate reader with a chemiluminescent detector.The results showed that some of the compounds showed good inhibition to Abl and Abl^T315I.In particular,these eight compounds?3a,3e,3m,3n,3p,4c,4f,4g?showed better activity.The most potent compound,3m,strongly inhibited Abl and Abl^T315I with IC₅₀??M?valued 1.273 and 39.89.At the same time,the control drug Imatinib showed excellent efficacy against Abl with an IC₅₀??M?value of 0.398,which was ineffective for the T315I mutation.The anti-proliferative activity of the synthesized target compounds against CML cell line K562,imatinib-resistant K562/R,T315I mutant BaF₃-ABL-BCR-T315I and human normal liver cell line L02 were tested by MTS assay.The results showed that most of the compounds had inhibitory effects on K562 and K562/R cells,especially the compound3m,its IC₅₀??M?were 8.32 and 7.308.Compounds 3m,3n and 3p for BaF₃-ABL-BCR-T315I cells also had good inhibition rate with IC₅₀??M?of 36.59,19.12 and 19.75.All compounds had a weak effect on human normal liver cell L02,and their IC₅₀??M?were above 100.