Synthesis And Antitumor Activity Of Structurally Simple Phenanthridine Analogues Based On Nitidine

Zanthoxylum nitidum,locally called‘liangmianzhen',is one of traditional Chinese medicines.Nitidine chloride which is isolated from the root of Zanthoxylum nitidium as the main active constituent exhibits potential anti-malarial,anti-inflammatory,anti-bacterial,antioxidant,anti-HIV,cardiovascular protection and especially anti-tumor biological activities.The nitidine can suppress the activation of several signal pathways for instance AKT,ERK,JAK,SHH and FAK,etc...resulting in the promotion of apoptosis,inhibition of cell proliferation and tumor angiogenesis.Due to the excellent antitumor activity for several types of cancer cells such as liver cancer,lung cancer,gastric cancer,renal cancer,breast cancer and so on,more and more attentions have been foused on the promising drug candidate.However,nitidine chloride directly from the plant has not only low water solubility and low bioavailability,but also low extraction yield and high commercial available cost that restricts the further study.Nowadays,chemists commit themselves to modifying the structure of nitidine,exploring efficient and versatile total synthetic routes to the analogues and evaluating structure-activity relationship.Therefore,it is the main direction of current research to modify and modify the structure with the nitidine simple structure as the skeleton in order to obtain new compounds with higher anti-tumor activity and less toxicity.The main research work and results of this paper includes the following parts.1.Using a nitidine as a lead compound,based on a fully synthetic route,we modified the structure of nitidine:?1?Introduction of nitrogen heterocycles at the C-6position of the nitidine nucleus;?2?Introduction of an alcohol group at the C-6position of the nucleus.Although neither attempt was successful,it also opened up new ideas for the subsequent synthesis of phenanthridine derivatives based on the nitidine nucleus.2.2-bromo-4,5-dimethoxybenzoic acid and various commercial anilines?m-aminoanisole,5,6,7,8-tetrahydro-1-naphthylamine,4-fluoroaniline,methyl4-aminobenzoic?as starting material,based on the synthetic route of the nitidine.A total of 47 novel compounds were synthesized by process optimization and route screening.The structures of the synthetic compounds were confirmed by ¹H-NMR,¹³C-NMR,ESI-MS,IR and elemental analysis.3.The antitumor activity against human cancer cell lines?HepG2,A549,NCI-H460and CNE1?was performed by MTT assay in vitro.The results showed that some of them had good anticancer activities,especially derivatives with a[?dimethylamion?ethyl]amino side chain in the C-6 position.Planar conjugated compounds 17a,17b,and 17c,with IC₅₀ values of 1.20?M,1.87?M and 1.19?M against CNE1 cells,respectively,were more active than nitidine chloride.Compound17b and compound 17c with IC₅₀0 value of 1.19?M and 1.37?M against HepG2 cells and A549 cells demonstrated superior activities to nitidine.Besides,compound 5e which had a phenanthridinone core displayed extraordinary cytotoxicity against all test cells,particularly against CNE1 cells with the IC₅₀0 value of 1.13?M.According to the antitumor activity results of the compounds,17a,17b,and 17c are expected to be anti-tumor lead compounds and deserve further study.The structure-activity relationship of the structure and activity of these compounds was preliminarily discussed,and the lead compounds with better activity and higher medicinal properties were further guided to lay the foundation for the development of innovative drugs.