Design,Synthesis And Antitumor Activity Of Novel Chemical Entities With Quinoline

Quinoline as a heterocyclic group with high biological activity,which has been widely used in the creation and development of pesticides and medicine.Quinoline is an important building motif for the development of new drugs.It is the structural core or pharmacophore of many innovative drugs and natural products.Quinoline derivatives have a variety of significant biological activities.Up to now,many quinoline derivatives have played an important role in the development of antitumor drugs,showed a good inhibitory activity on a variety of tumor cell lines,and have been clinically applied.Based on this,in this paper,three different series of new chemical entities with quinoline are designed,synthesized and the cytotoxic activity evaluation research is conducted in order to obtain lead molecules with highly active for the further development of new antitumor drugs.The main contents are described as follows:Chapter I:Research progress of antitumor chemical entities with quinoline.So far,many researchers have designed and synthesized a variety of quinoline derivatives.They can act on different targets such as topoisomerase,G-quadruplex,tubulin,histone deacetylase,protein tyrosine kinase,and PI3K-ATM-mTOR pathway,and a large number of quinoline derivatives have entered clinical evaluation.Therefore,designing and synthesizing new antitumor chemical entities with quinoline have certain research and development prospects.Chapter II:Design,Synthesis and Antitumor Activity of 7-Ethyl-10-fluoro-20-O-?cinnamate?-camptothecin Derivatives.Camptothecin is a class of alkaloids of natural product with quinoline.Our team found that 10-fluorocamptothecin had high antitumor activity.Based on the previous research,this chapter continue to use 10-fluorocamptothecin as a leading structure,and cinnamic acid group was introduced at its 20-position.A series of new 20?S?-O-?cinnamate?-camptothecin derivatives were designed and synthesized,and the antitumor activity of the obtained compounds was evaluated.The test results found that all target compounds showed significant antiproliferative activity on the three tumor cell lines tested,with IC₅₀ ranging from 0.01 to 49.87?M.Among them,3 and 5t are the most effective compounds in this series,showing good antiproliferative activity on three tumor cell lines with IC₅₀?compound 3:0.011,0.0085,0.012?M;compound 5t:0.010,0.016,0.019?M?,better than or equivalent to topotecan.The inhibitory effect of compound 3 and 5t on PC3 cell line was about 2.3 and 1.5 times higher than topotecan,respectively.It can be seen that compounds 3 and 5t are worthy of further study as drugs for the treatment of prostate cancer.Chapter III:Design,Synthesis and Antitumor Activity of Novel 6H-benzopyrano[3,4-b]quinoline Derivatives.Boeravinone natural products have a wide range of biological activities such as anti-inflammatory,antibacterial,antioxidant,antiviral and antitumor.However,its anti-tumor spectrum is narrow and its activity is weak,and further structural optimization or modification is needed to achieve the purpose of enhancing activity and expanding the antitumor spectrum.In this chapter,takeing Boeravinone natural products as the leading model,the new antitumor chemical entities with quinoline are designed and synthesized by introducing quinoline functional group into Boeravinone natural products by replacing oxygen atoms with nitrogen atoms,and the antitumor activity of the obtained compounds was evaluated.The test results found that such compounds have a broad antitumor spectrum,and most compounds affect the growth of human hepatoma cells?HepG2?,human colorectal adenocarcinoma cells?HCT116?,human pancreatic cancer cell lines?SW1990?,human breast cancer cells?MCF7?,human ovarian cancer cells?A2780?,and human cervical cancer cells?Hela?.Among them,7a,7d and 7g are compounds with better activity.7a has a high selectivity for Hela.Its IC₅₀is 4.37?M,which is about 3.6 times higher than the irinotecan(IC₅₀=15.61?M).7d showed good inhibitory activity against HCT116,its IC₅₀ is 10.9?M.7g showed good inhibitory activity against MCF7,and its IC₅₀ is 20.34?M,which was significantly better than irinotecan(IC₅₀=23.32?M).Chapter IV:Design,Synthesis and Antitumor Activity of 12-N,N-dimethylethyl-enediamine-6H-benzopyrano[3,4-b]quinoline Derivatives.N,N-dimethylethylenediamine has been widely used as an active functional group to optimize the structure of drug molecules.In particular,N,N-dimethyl-ethyl-enediamine group as an active splicing fragment often plays an important role in the development of antitumor drugs,such as TAS-103,ARC-111 and its derivatives.Based on Chapter 3,this chapter uses the"fragment-based drug design"method to introduce N,N-dimethylformate at position 12 of the 6H-benzopyrano[3,4-b]quinoline derivative.A series of derivatives were synthesized with ethylenediamine group,and their antitumor activity was tested.Among them,8c and 8d are the compounds with good activity,showing good inhibitory activity on HepG2 cell line,and their IC₅₀0 are 17.36and 19.84?M,respectively.Compared with 7c and 7f,8c and 8f significantly improved their antitumor activity.It has potential research significance and is worthy of further research.