Studies On Anticancer Activities And Molecular Mechanisms Of Several Novel 1,8-Naphthyridine Derivatives And Isoquinoline-1(2H)-imine Derivatives

Cancer has always been one of the most common causes of death in humans.Due to its wide variety and high spread,cancer treatment is often limited and the treatment effect is not satisfactory.For example,human melanoma has more than 232,000 cases per year.New cases have been discovered worldwide,and although 90% to 95% of early patients can be cured by surgery,these patients undergoing early radical surgery have a survival rate of less than 70% in the next 5 years;Breast cancer is currently one of the most common malignant tumors among women.Although people have been working hard on the treatment of breast cancer,the incidence and mortality of breast cancer have increased year by year in recent years,and the age of onset has The trend of youthfulness.Therefore,the research on effective treatment methods for cancer has always been the arduous task and mission of researchers.Many compounds have anticancer activity in their mother nucleus structure,and many compounds with this anticancer activity can be designed and utilized by human beings,thus introducing many functional groups with biological activity in order to endow the compounds with stronger anticancer activity.Therefore,the design and development of these new compounds are very promising.Among them,1,8-naphthyridine derivatives and isoquinoline-1(2H)-imine derivatives are the family of compounds with good anticancer activity.Based on this experimental background,we have carried out the following work: First,using a MTT method,a 1,8-naphthyridine derivative(named 3x)was applied to human melanoma cell line A375 and human normal fibroblast cell line HSF.The lethal activity test showed that 3x had a very strong killing effect on A375,but the toxicity to HSF was not very high.Therefore,we used Western Blot to explore the molecular mechanism of 3x-induced A375 cell death from the perspective of molecular biology.The results showed that 3x did not induce the death of A375 cells through Caspase family protein-related pathway,but rather increased and phosphorylated p53 by stimulating ser15 site of p53.After that,p-p53(Ser15)up-regulated the transcription and expression of apoptotic protein AIF and synergistic apoptotic protein Bax and PUMA genes,and AIF induced apoptosis with the cooperation of Bax and PUMA.It was also found that 3x inhibited the expression of XIAP in Caspase apoptotic pathway,which could be further studied in combination therapy.Secondly,four new isoquinoline-1(2H)-imine derivatives(named 10 r,10s,10 t,10u)were tested for the cytotoxicity of 9 different types of human cancer cell lines and normal human cell HSF by MTT method.The results showed that these four compounds had certain anti-cancer activity,but also had great killing effect on normal human cells.Compound 10 R has good killing activity on eight human cancer cell lines including MCF-7 cells,which can be further studied in the future.MCF-7 is a breast cancer model cell line that has been used for many years and lacks Caspase-3 and it is insensitive to many traditional drugs.Therefore,we preliminarily discussed the molecular mechanism of 10 R inducing MCF-7 cell death.It was found that 10 R induced MCF-7 cell death by pyroptosis,but not by classical pyroptosis pathway related to Gasdermin D and Gasdermin E.At the same time,we found that the lethality of 10 r and 10 t on MCF-7 cells was much greater than 10 s and 10 u.By comparing the chemical structures of these four isoquinoline derivatives,it is found that the 10 R and 10 t isoquinoline mother nuclei are connected by five-membered nitrogen heterocycles,while the 10 s and 10 u isoquinoline mother nuclei are connected by five-membered nitrogen heterocycles.The phenomena of great changes in pharmacological activities caused by the slight differences in chemical structures are also worthy of further study.