Design, Synthesis And Biological Evaluation Of PKB Inhibitors And Flavonoids Derivatives And Methodology Study

Cancer is one of the most major diseases that threaten to human life and health.Though there have been various antitumor drugs used in clinic, the problems of low specificity, high toxicity and multi-drug resistance still exsit. Therefore, it is still a hotspot in the research for new antitumor drugs with high efficiency, low toxicity and high specificity.Protein kinase inhibitors are a kind of effective antitumor drugs with specificity, and protein kinase B (PKB) is recongnized as one of the excellent targets for protein kinase inhibitors. PKB is a serine/threonine protein kinase belonging to the AGC superfamily of kinases. PKB, a key downstream component in the phosphatidylinositol-3 kinase (PI3K) signaling pathway, plays a key role in the regulation of cell survival, proliferation and growth. Activation or overexpression of PKB appears to be an important step in the form and development of many cancers. On the basis of structure features of PKB and the SAR of PKB inhibitors reported, we designed and synthesized 60 sulfonamides containing 1,2,3- triazole structure. All the synthesized compounds were examined for cytotoxic activity against human leukemia cell line HL-60.25 of them were evaluated further in four additional cancer cell lines (HepG2, A549, PC3, SGC7901). Most of the 25 compounds showed potent cytotoxic activities against the tested cell lines. Furthermore, the structure-activity relationships were discussed and a statistically reliable QSAR model(rcv2= 0.958, r2=0.64) was established by the CoMFA analysis performed. The model has good prediction. In addition,448 sulfonamides containing guanidine structure were synthesized from MBHA resin using a solid-supported approach. A combination of virtual screening results and structure diversity consideration,33 of them with good virtual screening results were chosen for the PKB inhibition assay in vitro. The biological test results showed that the inhibition activities of the tested compounds were not well, further biological screening on different targets is under way.Flavonoids, widespread in nature, are well-known for their good antitumor activities and low toxicity.23 flavonoid derivatives were designed and synthesized. The biological evaluation results indicated that some of the flavonoids derivatives possessed good antitumor activities. Among the compounds tested, compound 3.16 exhibited the most potent cytotoxic activity with IC50 values of 2.76-6.98μM. Further comparative molecular field analysis (CoMFA) was performed to conduct a 3D-QSAR study. The generated 3D-QSAR model could be a guide for further rational drug design. A novel and efficient metal-free carbon-nitrogen bond-forming coupling reaction between arylboronic acids and organic azides was reported. The reaction was fairly general for the preparation of secondary aromatic amines. Furthermore, the reaction was very functional-group tolerant. In addition, we have devoloped an efficient metal-catalyzed approach for the synthesis of 1,3-benzodiazepines on solid phase.