Design,Synthesis And Antitumor Activity Study In Vitro Of 1,3,4-oxadiazole Derivatives As Cannabinoid Ligand Compounds

Cancer has always seriously affected people's quality of life,and many of the chemotherapeutic drugs lead to a lot of toxic side effects on the body when they are used to treat cancers.Therefore,the development of new targeted drugs with high efficiency,high affinity and small side effects is of great significance for the treatment of tumors.Recently,many studies have shown that cannabinoid receptors are highly expressed in many tumor cells.When cannabinoid agonists bind to cannabinoid receptors,they can inhibit tumor growth by inhibiting tumor proliferation,metastasis,invasion,angiogenesis,and induction of apoptosis.In this thesis,based on the theoretical basis of computer-aided drug design and the in-depth study of the three dimensional crystal structure of cannabinoid receptors,using rimonabant as the lead compound,we design and synthesize 23 kinds of1,3,4-oxadiazole derivatives as cannabinoid ligand compounds.The target compounds are synthesized by the reaction of substitution,condensation,cyclization.The method is mild reaction conditions and simple operation.Their structures are confirmed by IR,¹H NMR and ESI-MS.The synthesized compounds are all new compounds which have not been reported in the literature.The preliminary activity was carried out in vitro.The experimental results showed that the compounds of 5f,7b,8e had good antitumor activity with the IC₅₀ values27.6?M,46.2?M and 54.4?M respectively,and the activity of 5f was similar to the positive control drug of WIN55,212-2 with IC₅₀ values 30.6?M.By docking the three dominant compounds with cannabinoid receptors,the compounds mainly produced antitumor activity by binding to the hydrophobic amino acid residue of the cannabinoid receptor.The result showed the rationality of the design idea and lays a solid foundation for the discovery of small molecule cannabinoid ligands with high activity and low toxicity in the future.