Design Of One, Three Stilbene Estrogen Receptor Antagonist, Synthesis And Structure-activity Relationship Study Phthalides Rearrangement Reaction

The estrogen receptor(ER) is a ligand-activated transcription factor that belongs to the steroid /retinoid family of DNA-binding intracellar receptors(ICR). Estrogen is an important endocrinal hormone secreted by ovary. It activates estrogen receptor leading to a series of biological events. When the level of estrogen is unbalanced, physiological function disordered, the level of estrogen being too high, inducing the growth of breast cancer. While the level is too low, Causing the osteoporosis et al. Study and development of the tissue-selective antagonist of ER is important not only for the understanding of molecular basis of the antagonism, but also for the prevention and therapy of the breast cancer, osteoporosis and cardivascular diseases .Tamoxifen is a typical estrogen receptor antagonist with the structure of triphenyl-ethylene, which is widely used in treatment of hormone responsive breast cancer. The use of tamoxifen and other antiestrogens suffers from serious limitations because of adverse effects.In order to improve the biological activity and reduce the side effects and toxicity, a new type of triphenyl estrogen receptor antagnist has been designed based on the lead compound—tamoxifen. The compounds with new scaffold mimic the topology of tamoxifen and spatial disposition of critical substituents. Forty-four noval compounds have been synthesized, among them there are thirty-seven target compounds.Inhibition of uterus growth has been evaluated by the target compounds. The results showed that some of them are antagonists, which inhibit the uterus growth; others are agonists which promote the uterus growth. Compounds â„– 14 and 21 are superior antagonists to tamoxifen.The relative binding affinity to estrgen receptor has been evaluted by some of the target compounds. It indicated that all of the test compounds can interact with estrogen receptor(IC₅₀>10^-6mol/L), especially compound â„– 35 with IC₅₀ 10^-8mol/L.The results from 3D-QSAR of 13 compounds revealed that the steric field is very important for the interaction between the compound and the receptor . The CoMFA model indicated that enlargeing the alkyl in nitrogen in size favoured to the affinity, and the large group in para postion in the phenyl ring A is disfavoured.