4-styrylpyridine Analogs: Synthesis And Evaluation Of Anticancer Efficacy

Malignant tumor is a severe threat to human's health and life. The prevention and treatment of cancer has become a great challenge to scientists. With the thorough research of tumor mechanism, drugs acting on cell signal transduction pathway began to attract attention of researchers as an important target for anticancer drug development. PI3K/Akt signaling pathway involved and regulated apoptosis, proliferation, differentiation and metabolism. Continued activation of Akt is considered as decisive factors of the growth and survival of tumor cells. Thus, blocking the continued activation of this pathway provide a new strategy for cancer treatment. Inhibitors targeting this signaling pathway became a potent therapy for the tumors caused by the activation of PI3K/Akt signaling pathway.Serine/threonine protein kinase Akt, as a downstream target for PI3K, had a high expression in most tumor cells, such as ovarian cancer, breast cancer, pancreatic cancer and leukemia cells. The activated Akt phosphorylated a series of substrates, which could block apoptosis pathway, promoting cell proliferation, accelerating the occurrence, development and transfer of tumor cells, maintaining the survival of tumor cells. Akt inhibitors had become a hotspot now. A number of small molecule compounds with different mechanisms have been reported, but none of them were come into market.Our group had done a research on the crystal structure of Akt to analyse the interactions between inhibitors and Akt. Useing fragment-based drug design and computer aided drug design, hydrogen-bonding acceptor group, the narrow hydrogen-bonding donor and the long-chain amino group were connected on a flat aromatic structure, leading to a series of 4-styrene-pyridine derivatives.The target compounds were synthesized from substituted salicylaldehyde, and obtained via condensation reaction, hydrolysis reaction, etherification reaction, acylation reaction, sonogashira reaction, amino protection and deprotection reaction. These compounds have not been reported before, and the structures were identified by MS, IR and 1H-NMR spectra. These compounds showed good activity against K562 tumor cells in vitro. Among them, the best one was vii-5 which IC50 is 4.34±1.04μM, and then vii-4 which IC50 was 6.35±2.83μM. Next we will determine Akt kinase inhibitory activity of these compounds.The structure-activity relationships of these compounds indicated that pyridyl group on the 4-styrene pyridine ring was necessary for the activity; The activity was better when the amino side chain on the benzene ring was flexible, and without rigid ring closing to amino; The biological activity would also increase when using chlorine or bromine atoms to replace para position of the side chain.The information gathered from this thesis will be useful in the research of structure optimization and drug screening in the future.