Synthesis And Protein Tyrosine Kinase Inhibitory Activity Evaluation Of Aryl Benzyl Sulfones Derivatives

Protein tyrosine kinases(PTKs) play an important role in the process of tumor cell proliferation,inhibiting its activity can inhibit tumor cell growth or induce apoptosis. Protein tyrosine kinases are important targets for cancer treatment, there are already a dozen small molecule tyrosine kinase inhibitors with good anti-cancer effects approved marketing. Studies of small molecule tyrosine kinase inhibitors are promising.Ex-Rad mainly plays an important role in the ATM-p53 pathway, has entered a clinical trial of radiation protection agents. p53 is a well-known gene for inhibition of cancer. Meanwhile, a variety of tyrosine kinases in some signaling pathways are also inhibited by Ex-Rad. In this paper, Ex-Rad was used as a lead compound and 102 compounds based on the structure of Ex-Rad were designed and synthesized. Preliminary evaluation of their tyrosine kinase inhibitory activities was done. The main findings are as follows:1. Ex-Rad was used as a lead compound, 102 aryl benzyl sulfone compounds, including 51 sulfoxide compounds and 51 sulfone compounds, were reasonable designed and synthesized by analyzing the structure-activity relationship of Ex-Rad and using bioisosteres principle. Using benzyl halide and thiols as the raw materials and through thioetherfication, we got sulfides. Finally, at a suitable temperature, sulfones or sulfoxides were synthesized by oxidating sulfides in acetic acid with an appropriate amount of hydrogen peroxide. The structures were confirmed by 1H-NMR.2. Preliminary evaluating tyrosine kinase inhibitory activity of the 102 compounds by the high-throughput screening model for tyrosine kinase inhibitors and we found that sulfones and sulfoxides containing indolone structures generally have good inhibitory activities in the concentration of 100μM or 10μM,the activities were much stronger than the lead compound Ex-Rad. What’s more, the inhibitory activities of part of these compounds were even stronger than L029(L029, being confirmed with good tyrosine kinase inhibitory activity, was synthesized in our laboratory). The tyrosine kinase inhibitory activities of sulfones and sulfoxides containing naphthalene structures were weak, only showed significant inhibition in the concentration of 1 mM, but some of them were still better than the lead compound. While in the concentration of 100μM, the inhibitory activities were very weak.3. Through the analysis of the results for screening, we found sulfones and sulfoxides containing indolone structures generally have strong inhibitory activities, no significant difference showed between sulfones and sulfoxides. Introducing a group(such as methyl or halo) in the the ortho position of benzene ring would reduce its inhibitory activity, introducing the group in the the meta or para position of benzene ring had no significant effect; After introduced bromine in the 5 position of indolinone structure, introducing the group in the meta position of benzene ring would reduce its activity, but in the ortho or para position, it showed no significant effect.The tyrosine kinase inhibitory activities of sulfones and sulfoxides containing naphthalene structures were weak. Introducing a group(such as halogen or methyl) in the meta and para position of benzene ring would enhance its inhibitory activity, it showed no significant effect when introducing in ortho position; After the introduction of bromine in position 6 of naphthyl structure, no significant effect on the inhibitory activity, and then introduced other groups(such as halogen or methyl) in benzene ring, when in the ortho position, there was no significant effect on the inhibitory activities, while in meta or para position would significantly enhance their inhibitory activities.