Design,Synthesis And Biologicai Evaluation Of Quinoxaline/Quinazolines As Small-molecule Inhibitors Targeting Phosphoinositide3-kinase(PI3K)

Cancer is becoming the number-one threat to human health worldwide. Traditional anti-cancer agents, which directly interfere with mitosis, DNA synthesis, and repair systems, are often connected with drawbacks such as low efficacy and high toxicity. Small-molecule inhibitors targeting key knots of cellular signaling pathways are new class of anti-cancer agents. These small-molecule inhibitors may be more effective than current anti-cancer treatments and less harmful to normal cells. Phosphoinositide3-kianses (PI3Ks) are family of lipid kinases that regulate crucial cellular events such as proliferation, survival, growth, metastasis and apoptosis. Extensive studies have established the close connection between tumor genesis&progression and the a isoform of PI3Ks, making PI3Kα a promising target for cancer treatment. Consequently, the research on small-molecule PI3K inhibitors has attracted considerable attention in recent years.Enlightened by the structural features and binding mode of PI3K inhibitors, using the quinoxaline core presented in reported inhibitors, target compounds were constructed through the introduction of different arylamino moiety into the2-position and either arylsulfonyl or arylsulfonylhydrazide group at the3-position of the quinoxaline core. Herein, series of53novel N-arylquinoxalinylamine derivatives were synthesized and biologically evaluated for their in vitro anti-tumor activities, the result of which showed that most target compounds exhibited better anti-proliferation activity against tested cell lines than that of the positive control and some compounds (e.g.1-27,1-51and1-61) exhibited nanomolar potency. Preliminary SAR study revealed that compounds with a3-arylsulfonyl substituent exhibited better activity than that with a3-arylsulfonylhydrazide substitutent and the introduction of methoxy, amino, and hydroxyl group at the2-arylamino group was beneficial for potency. Enzymatic assay against PI3Ka showed that compound1-27(IC50:0.07μM) and compound1-61(IC50:0.47μM) exhibited potent PI3Ka inhibitory activity.Based on the results obtained above, a PI3Ka pharmacophore model Hypol was established using Catalyst software package, followed by virtual screening against databases. Then series of93aliphatic-cyclic-aminoquinoxalines were designed and synthesized based on the structural features of a virtual-screening identified potent morpholinoquinoxaline compound WR01(2-30) according to principles of bioisosterism and design of analogues. In vitro evaluation against human cancer cell lines showed that most target compounds exhibited better anti-proliferative activity than that of the positive control. PI3Ka assay showed that hydroxylpiperidinylquinoxaline (e.g.2-72, IC50:0.077μM;2-75, IC50:0.025μM) and various piperazinylquinoxaline derivatives exhibited potent inhibitory activity against PI3Ka. The experimental data of PI3Ka assay were consistent well with the pharmacophore-based predicted values, which validated the accuracy of the established model Hypol. A following assay showed that2-75exhibited significant suppressive effect against Akt phosphorylation. The above results demonstrate that2-75is a promising PI3Ka inhibitor.Besides, based on reported2-phenyl-4-morpholinoquinazoline PI3K inhibitors, five series of49novel morpholinoquinazoline derivatives were designed and synthesized in this study according to combination principle through the introduction of arylideneamino, arylsulfonylamino, dioxopyrrolidinylamino, and maleinimide chains into the6-position of the morpholinoquinazoline core. In vitro anti-tumor evaluation revealed that the presence of the2-phenyl group was beneficial for potency, compounds with an arylsulfonylamino chain showed better activity than that with an arylideneamino chain, dioxopyrrolidinylamino substituted compounds showed moderate potency, and compounds substituted by maleinimide chains (e.g.3-68and3-69) showed potent inhibitory anti-tumor activity. This study provides new insights for the development of quinazolines as anti-cancer agents.