Syntheses And Anti-tumor Activities Of Novel Quinoxaline Derivatives As PI3K Inhibitors

Phosphoinositide 3-kinase(PI3K)is an intracellular phosphatidylinositol lipoprotein kinase.The PI3K-mediated PI3K/AKt/m TOR signaling pathway regulates many physiological processes such as cell growth,differentiation,apoptosis,and blood vessel growth.Dysregulation or abnormal activation of the pathway has been confirmed to be closely related to the development of a variety of malignant tumors(such as breast cancer,gastric cancer,cervical cancer,prostatic carcinoma,colon cancer,etc.),and thus PI3K has become one of the targets for tumor treatment.At present,PI3K is mainly divided into class ?,class ? and class ?.Among them,the study of class ? PI3K is most concerned.According to the difference in structure and function,class ? PI3K can be further divided into two types: IA and IB.Among them,class IA has three subtypes: PI3K?,PI3K?,and PI3K?,which are composed of corresponding catalytic subunits PI3K?,PI3K?,and PI3K?(corresponding to PIK3 CA,PIK3CB,and PIK3CD)and the regulatory subunit P85.PI3K? and ? are expressed ubiquitously.PI3K? is often used as a target for the treatment of various malignant tumors,due to the prevalent mutation amplification of PIK3 CA.PI3K? isoforms are associated with platelet aggregation,thrombosis,and insulin signaling,and the dysregulation of PI3K? can trigger thrombotic disease.PI3K? is highly expressed in B-cell.Aberrant activation of PI3K? could promote lymphoma and multiple myeloma.With the exploration for structure and biological function of PI3Ks,various PI3K inhibitors with different scaffolds and isoform selectivity have been discovered one after another,which are helpful for the treatment of tumors,thrombosis and immune-related diseases.This article is dedicated to the discovery of novel PI3K inhibitors.In this paper,the characteristics of P110? pocket were studied with the help of computer-aided drug design software.The structure of the lead compound XL-765 was modified and a series of quinoxaline-like small molecule compounds were designed and synthesized,which was based on the characteristics of the pocket.The main content of this dissertation was listed as below:(1)The preparation of novel compounds with quinoxaline core structures.There are more than 31 types of 2,3-disubstituted quinoxaline-analogs were synthesized.By using o-phenylenediamine or o-phenylenediamine as strating materials.After cyclization with diethyl oxalate in the presence of HCl,the corresponding products were chlorination by SOCl2 and reacted with a variety of substituted phenols in sequence.Then,the affording products were treated with hydrazine hydrates,arylsulphonyl chloride or aryl chloride step by step.The desired products were given in good to excellent yield after purification.(2)These target products were fully characterized by IR,MS and NMR,respectively.(3)Human non-small cell lung cancer A549,human gastric cancer cell SGC-7901,human colon cancer cell HCT-116 and human breast cancer cell MCF-7 were selected as research subjects,and the anti-tumor activity of target products was preliminary screened by MTT assay.(4)7e and 7i displayed higher anti-tumo activities than other compounds.By using SYBYL-X.1.3 and Py Mol software and PI3K subunit P110?(PDB code: 5DXT)as the target enzyme,the hydrogen bonding modes of compounds 7e and 7i with enzyme were discussed and the reason was elucidated.The results in this dissertation indicated that: 1.These final products were confirmed by the analysis of IR,MS and NMR,respectively.To the best of our knowledge,they have not been reported previously elsewhere.2.Preliminary screening of target products by MTT assay showed that compounds 7e,7i,and 18 b had good inhibitory activity against four tumor cells,of which 7e had better activity than the control group LY294002.3.The software docking analysis showed why the target product's activity is lower than the existing PI3K? inhibitors is likely to be related to the hydrogen bonding mode and spatial extension in the active site.