Study On The Synthesis Of Azasteroid Analogues And Cabozantinib

Cabozantinib is a new targeted drug developed by Exelixis Biopharmaceutical Co Ltd in the United States.It was approved by the FDA in 2012,which is a small molecule tyrosine kinase inhibitor.The.key intermediate of cabozantinib can be prepared by nitration,reduction,cyclization and chlorination in the presence of 3,4-dimethoxyacetophenone as the starting materials.The synthesis of cabozantinib is carried out by chlorinated and amidated et al.Some of the reaction conditions are well optimized.The preparation of key intermediates is a new method,easy to obtain the raw materials,mild reaction conditions with high yield and commercial value.The development of the synthesis process has potential application prospects.Sterols,with good biological activitives,are a kind of molecules having unique frameworks which are widely distributed in nature and in vivo.The anti-tumor activitives of these molecules are prominent,however,long-term uses of these may cause the dependences and resistances on drugs.Thus they have great limitations to be designed as medicines.Heterocyclic compounds are widely used in the design of new molecules in drug design result from their special carbon skeleton configurations.Some scientific research may suggested that the introduction of heteroatom in steroidal A and D rings could effectively enhance the bioactivity of steroid molecules and then improve their anti-tumor effects.In view of the better experimental expectations for nitrogen-containing heterocyclic molecules,we expect to use the existing steroidal molecules to produce a class of nitrogen-containing heteroatoms as a similar structures derived from their parent molecules through some structural modifications and drug design methods.These new-designed structures can be used to build a series of new compounds,so that it can both have the good biological activity and reduce the drug dependences of steroids.Based on this idea,in the second part of this paper,we select the cheap natural products as the starting material.By the lactone ring opening,oxidation and lactam three-step reactions to build a new molecular skeletons containing lactam construction.Then we get a dozen of new molecules through further structural modifications.The structures of the compounds were characterized by NMR and HRMS.Further molecular design,synthesis and preliminary studies on antitumor-effect relationships are still ongoing.