Synthesis, Structure And Activity Relationship Of The Novel P13K Anti-tumor Inhibitors

Intracelluar signal transduction plays an important part in the process of celluar metabolism, segmentation, differentiation and death. Overactive signal transduction relates to tumor development and progression. PI3K/Akt pathway is an important signal transduction pathway, it plays important parts in cell apotosis and survival by affecting the activity of downstream effector molecules, and is closely associated with the development and progression of human tumors, since PIEKsare shown to be mportant targets in cancer, development of PI3Ks are shown to be important targets in cancer, development of PI3K inhibitors has attracted more attention thanever before. In recent years, a large mount of PI3K inhibitors have already entered clinical trials, including GSK2126458, SF-2226, NVP-BEZ235, XL-147, PX-866, GDC-0941, ZSTK474 AND GSK-615.BIBW-2992, a new class of PI3K inhibitors against EGFR and HER2, the IC50 against natural, sustainablem, and dual sustainable H1666, H3255, NC1187 is, 6,93 nM, which is under II period clinical study and to treat mammary carcinoma and rectum carcinoma. We change the ring in order to see whether the activity is improved.The synthesis of GSK2126458 is long and tedious, we use 2,2-dimethyl-1,3 -4,6-dione instead of Diethyl 2-(ethoxylmethyl-ene)malonate, the temper- aute is reduced and the process is shortened, sonagashira reaction and Diels-Alder reation were used to the formation of the ring of pyridazine,the precious pyridazin-yl-4-boronic acid was avoided..Based on the above considerations, a novel series of BIBW-2992 analogues (TM1-TM7 have not been reported) were synthesized and evaluated for their in vitro anti-proliferative activity to find new anticancer candiates with more potent activity than BIBW-2992.The analogues were identified and confirmed by HPLC, HNMR, and ms.The anti-proliferative studies showed that most of the compounds displayed more potent activity than BIB2-2992, Furthermore, pharmacokinetic properties of the selected compounds were also disclosed . But the result was not disirable ,further optimization fo this new series of PI3K inhibitors is ongoing in our laboratory.