Synthesis And Anti-leukemia Activity Of 4-anilinoquinazolines Derivatives

PTKs (tyrosine protein kinases) are central to the signal transduction machinery of healthy cells and their growth, differentiation, mitosis, and apoptosis. However, functional abnormalities of PTKs will result in signal abnormalities, cell overexpression, anti-apoptosis, then improve the creation and development of malignancy. So, the PTKs serve as molecular targets for many of the investigations new agents.JAKs (Jauns kinases) are cytoplasmic PTKs that play pivotal roles in the initiation of cytokine-triggered signaling events by activating through tyrosine phosphorylation the STATs (Signal Transducers and Activators of Transcription protein) and forming JAKs- STATs pathway.JAK3 (Janus kinase 3) is expressed constitutively at high levels in lympho- hematopoietic system, specially associates with theγc receptors of IL-2 receptor and is activated by the cytokines IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 that share theγc receptor. It plays an important role in normal lymphocyte development and function. JAK3 misfunction has been linked to ALL (acute lymphoblast leukemia). The inhibitors of JAK3 as a new class of anti-leukemia agent have immunosuppressive and anti-inflammatory properties.JANEX-1(WHI-P131) is a potent and selective inhibitor of JAK3, which belongs to 4-anilinoquinazolines, IC50=9.1μM. Using methyl 2-amino-4,5-dimethoxy benzoate as the stanting material, JANEX-1 was synthesized through the Niementowski reaction, chlorination, alkylation, and neutralization reaction, yield: 34.3%, the structure of which was confirmed by 1H-NMR,IR,MS. This synthetic route has never seen in any documents.Using the binding model between 4-anilinoquinazoline compounds and kinase domain of JAK3, basing on JANEX-1 as lead compound, we design and synthesis two classes compounds which have not seen in any documents: Ten of 4-[(6,7 -dimethoxyquinazoline-4-yl)amino]phenolic ester and Eight of N-[4-(phenylamino) quinazoline-7-yl]amide. Eighteen target compounds were synthesized, all of which were confirmed by 1H-NMR,IR and EI. In addition to this, six of important intermediates were synthesize. The structure of that was confirmed by 1H-NMR.Using MTT method, the synthesized target compounds were tested for their inhibitory activity towards the human leukemia cell line K562. The result showed that the compounds substituted at 7-amino for example Y3 (64.47%) and Y5 (75.85%) have better inhibitory activity than JANEX-1 and other target compounds. Further immunosuppressive activity, in vivo anti-leukemia pharmacological texts and mechanism researches are underway.