Yl Series Of Anticancer Drugs. Three New Nitrogen Synthesis And Activity,

Intracelluar signal transduction plays an important role in the process of celluar metabolism, segmentation, differentiation, biological behaviour and cell death. Overactive siganal transduction relates to tumor development and progression. PI3K/Akt pathway is an important intracellular signal transduction pathway, it plays important roles in cell apotosis and survival by affecting the activity of downstream effector molecules, and it is closely associated with the development and progression of human tumors. Since PI3Ks are shown to be important targets in cancer, development of PI3K inhibitors has attracted much attention. In recent years, several PI3K inhibitors have already entered clinical trials, including PX-866, SF-1126, NVP-BEZ235, XL-147, GDC-0941, ZSTK474, GSK-615 and GSK2126458.As a new class of PI3K inhibitors, thieno[3,2-d]pyrimidine derivatives have been extensively studied. Through the synthesis and biological evaluations of this series compounds, GDC-0941 was found to have potent activity with IC50 of 3,33,3 and 75 nM against PI3Kα,β,δand y respectively, and GDC-0941 is currently being evaluated in human clinical trials for the treatment of cancer. GDC-0941 selected as the lead compound,4-methanesulfonyl-piperazin-1-ylmethyl substitutent was replaced with a variety of substituted triazoly groups to investigate whether heterocyclic aromatic group can replace the non-aromatic piperazine group. In addition, various tertiary amine fragments were introduced into the triazole groups as side chains to maintain water-solubility. Furthermore, compounds, some replacements of indazole substitutent in GDC-0941 was also carried out to find a desired alternative fragment. Based on the above considerations, a novel series of GDC-0941 analogues(TM1～16) were synthesized and evaluated for their in vitro anti-proliferative activity to find new anticancer candidates with more potent activity than GDC-0941. The analogues were identified and confirmed by HPLC,1HNMR and MS.The anti-proliferative studies showed that most of the compounds displayed more potent activity than GDC-0941. Further, pharmacokinetic properties of the selected compounds were also disclosed herein. But the result was not desirable, further optimization of this new series of PI3K inhibitors is ongoing in our laboratory.