Derivatives As NAChR Agonists And Analogues Designed Based On Skeleton Warp As Dual EGFR/HER-2 Inhibitors: Synthesis And Activity Evaluation

In this paper, analogues based on compound 4OH-GTS-21 have been synthesized to develop potential a7nAChR agonists; derivatives of salicylic acid as the core framework have been synthesized through structural modification to develop EGFR/HER-2 dual inhibitors.a7nAChR has been recognized as a potential therapeutic target for the treatment of a variety of pathologic conditions, including Parkinson's disease, Alzheimer's and pain.4OH-GTS-21 has been proved to be selective a7 receptor agonist and played importent role in cell protection in humans and mice. Because a7 nicotinic acetylcholine receptor (a7nAChR) distributed mainly in rat hippocampal slices CA1 district intermediate neurons membrane, and because of increased polarity of 4OH-GTS-21, it is difficult to through the blood brain barrier (BBB), which resulted in low bioavailability. We decided to modify the 4OH-GTS-21with sugar moieties to solve the problem mentioned above.1. Analogue of 4OH-GTS-21 (G15) was obtained from 2,4-dihydroxybenzaldehyde as the starting material through five steps in total yield of 14.7%. found that G15 can significantly enhance the EPSP in hippocampal CA1 area, and has the potential function to improve learning and memory.2. Three new compounds 1,2-trans-glycoside derivatives were synthesized and two new compounds 1,2-trans-glycoside derivatives with truss arm were synthesized. All derivatives of 4OH-GTS-21 showed the inhibition of EPSP effect.Epidermal growth receptor EGFR and HER-2 has become a new target for anti-cancer therapy, One newly listed anilinoquinazoline drug Lapatinib is also inhibited EGFR and HER-2 tyrosine kinase as a dual inhibitor attracted great attendion.Based on the skeleton of anilinoquinazoline we dsigned and completed a series of salicylamide drivatives and its antitumor activity was tested for QSAR studies and drug research foundation. We also designed another two flavonoid and isoflavone derivatives, preliminarily studied its synthetic route and method.1. Synthesized three 4-and 5-salicylamide derivatives with long chain and studied their EGFR/HER-2 dual inhibitory activities, they all only have EGFR inhibitory activity.2. Synthesized fourteen 5-furan substituted salicylamide derivatives with long chain (S-4-S-18) and found only S-4 kept EGFR/HER-2 dual inhibitory activities.3. All derivatives of salicylamide were tested the effect of EGFR/HER-2 dual inhibitory activities. And found that the activity of 4-aniline part macromolecular substituted compound S-4 is higher than small molecules substituted compound S-10-S-17; the activity of 3-aniline part small-molecule electrophilic substituted compound S-4 is higher than electron donor substituted compound S-7.4. Explored a synthetic route of flavonoid derivatives used for the synthesis of compound S-24 and S-25.