| The programmed necrosis of the cell ruptures the cell membrane and releases pro-inflammatory factors,which is the main cause of human inflammatory diseases and tumors.Receptor interacting protein 1(RIPK1)activates nuclear factor-κB(NF-κB)plays a key role in signal transduction such as apoptosis and programmed cell necrosis.Related studies have found that the ubiquitination of RIPK1 can activate NF-κB,which has attracted widespread attention.At present,RIPK1 inhibitors are still in the preclinical research stage,so it is urgent to develop new RIPK1 inhibitors with stronger specificity.The compound GSK2982772 is a highly effective RIPK1 inhibitor for the treatment of inflammatory diseases.In this project,the compound GSK2982772 was used as the lead compound,and 28 target compounds were designed and synthesized through the principle of bioelectronic isostere.All target compounds were characterized by MS,1H NMR and13 C NMR.In addition,the compounds were screened for activity by inhibiting the activity of RIPK1 in vitro.With GSK2982772 as the positive control,the results showed that most of the target compounds did not exhibit RIPK1 inhibitory activity,and only compound 13 a and compound 17 showed RIPK1 inhibitory activity,which was weaker than that of the positive control.Then,some compounds were docked with RIPK1 to discuss their structure-activity relationships.Although the target compounds have no RIPK1 inhibitory activity,it also provides a useful exploration for the development of RIPK1 inhibitors.Ischemic stroke is a major disease caused by blood supply blocked by the brain and seriously endangering human health.It has the characteristics of high incidence rate and high mortality.3-n-Butylphthalide is an effective component of traditional Chinese medicine extracted from celery seed.It is the first class of new drugs with independent intellectual property rights in the field of cerebrovascular disease in China.It has a variety of biological activities including anti-platelet aggregation,anti-thrombosis and improving cerebral microcirculation.Ferulic acid is a small active molecule extracted from Ligusticum chuanxiong Hort.It has many pharmacological activities,such as antioxidant,anti-inflammatory,anti-platelet aggregation and so on.In this project,12 novel 3-n-butylphthalide derivatives were designed and synthesized by linking the alkane chain of 3-n-butylphthalide with the phenolic hydroxyl group of ferulic acid and inserting different substituents into the benzene ring of ferulic acid.All the target compounds were characterized by ESI-Ms,13 C NMR and1 H NMR.The protective effects of these compounds on rat cortical neurons were evaluated by OGD / R-induced injury experiment,and the compounds with excellent protective activities were selected to evaluate their anti-platelet aggregation activities.The results showed that all compounds showed a certain degree of protection in OGD/ R-induced cortical neuron injury.At the dose of 1 μmol ·L-1,the cell survival rates of compound 21 b and compound 21 e were 81.78% and 81.36%,respectively,which were higher than that of the positive control 3-n-butylphthalide.Therefore,compounds 21 b and 21 e were selected to test platelet aggregation activity induced by arachidonic acid and adenosine diphosphate.The results showed that the IC50 of compounds 21 b and 21 e were 0.110 m M and 0.398 m M respectively in arachidonic acid-induced platelet aggregation test,and their pharmacodynamic activity was slightly lower than that of aspirin.In the ADP induced platelet aggregation test,the IC50 of 21 b and 21 e were 0.301 m M and 0.573 m M,respectively.The antiplatelet aggregation activity of 21 b and 21 e was better than aspirin.The above results show that the 3-n-butylphthalide derivatives designed in this project have certain reference value for the drug research and development in the treatment of ischemic stroke. |
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