Design, Synthesis And Biological Activity Of Novel Substituted Aminophenol Compounds

Breast cancer is the most common cancer clinically today, and it is also a leading cause of cancer-related death, which has a threat to women’s physical and mental health. It is very important to find ideal drugs with high efficiency and low toxicity.Estrogens and their main targets, estrogen receptors (ERa and ERβ) were well recognized to play critical roles in the progression of breast cancer. The remarkable tissue-selective effects of estrogens has led to the development of compounds called selective estrogen receptor modulators (SERMs), which mainly function as estrogen agonists in bone, brain and the cardiovascular system, but as antagonists in breast and uterus. Because of the special concerns, the interest in the development of SERMs has been increasing in recent years.The traditional antifungal drug ketoconazole was found having selective estrogen receptor modulating activities by computer-aided drug design. It is found that 1,2,3-triazole and phenolic hydroxyl group are essential to improve the activities of these compounds. So compounds A were designed and synthesized by introducing these two groups. Based on the pharmacological activity results of compounds A and the QSAR of classical selective estrogen receptor modulators, the enantiomers B and C were designed and synthesized.Intermediate 10 was prepared from 2-fluoro-4-hydroxyacetophenone followed by benzyl protection, bromination, ketal reaction, hydrolysis reaction and separated from silica gel column chromatography, while compounds A was got via click reaction. The compounds B and C were synthesized by using a chiral auxiliary camphorsultam as a controlling reagent. Intermediate 20 was synthesized from Methyl 4-hydroxyphenylacetate through the reaction of protection, hydrolysis. The important chiral intermediate was got via asymmetric synthesis, then target compounds were synthesized through reduction reaction and nucleophilic substitution reantion et al. All the 43 compounds of three series were first synthesized and reported. The structure of all the compounds were confirmed through 1H NMR, partly were confirmed by 13C NMR and MS.The MTT assay was used for measuring the pharmacological activity of the 43 compounds. The preliminary study of SAR was showed that Compounds A exhibited poor activity, which contains complicated side chains may affected the binding way of the target enzyme. The side chains of compounds B and C with the small steric hindrance may result in the high activities. The group of piperazine from compounds B and C may contributed to the inhibitory effect to the cancer. Some differences were found from the enantiomers in the expression of pharmacological activity.The potent compounds B5、B7、B11、B12、C11、C14 were deserved further studies for their better activities.Enzyme activity is in preparation now.