Design, Synthesis And Antitumor Evaluation Of Novel Naphthalimide Derivatives

Naphthalimide derivatives have made great progress as anti-tumor agents.Some representative compounds such as Amonafide,Mitonafide,DMP-840 have entered phase Ⅱ clinical,but cancer drug resistance and serious side effects also limit further clinical practice application.In this paper,the research progress of naphthalimide antitumor agents was reviewed.On the basis of this,a series of 67 naphthalimide derivatives of C-4 position end-modified piperazine were designed and synthesized.Structural characterization was carried out by means of ¹HNMR,¹³C NMR,HRMS and it was confirmed that it was the target compound.The cytotoxicity in vitro of 67 naphthalimide compounds against MGC-803,SKOV3,HepG2,T24,A549,SMMC-7721 tumor cell lines and human gastric mucosal cell line GES1 were tested by MTT assay.The results showed that all the 67compounds showed high levels of inhibitory activity against MGC-803,SKOV3,HepG2,T24,A549,SMMC-7721 tumor cell lines.The inhibitory activities of compounds NA19,NA1A,NA29,NB01 and NB21 on human gastric cancer MGC-803 cells were 5.23±0.66μM,5.73±0.49μM,3.04±0.27μM,1.41±0.11μM,0.86±0.16μM,apparently superior to the anticancer activity in vitro of the positive drugs Amonafide（9.06±0.45μM）and Mitonafide（6.81±0.75μM）.The in vitro antitumor activity of the compounds NA19,NA1A,NA29,NB01 and NB21 against human bladder cancer T24 cell line was 3.03±0.48μM,0.59±0.06μM,and 2.08±0.25μM,0.33±0.07μM,0.42±0.05μM,which was obviously superior to the positive drug Amonafide（5.01±0.47μM）.Notably,NA19,NA29,NA1A effectively suppressed tumor growth in a mouse xenograft model.The experimental results showed that the tumor inhibition rates of compounds NA19,NA29 and NA1A were 56.3%,64.5%,and 57.1%,respectively,and the tumor inhibition effect was slightly worse than that of Amonafide（the inhibition rate was 70.6%）.The potential targets of naphthalimide derivatives are DNA and topoisomerase.The interaction of compounds NA19,NA1A,NA29 with DNA and topoisomerase Ⅰ was studied by agarosegel electrop horesis.The results of agarosegel electrop horesis experiments of NA19,NA1A,NA29 and DNA showed that there was a strong interaction between compound NA1A and DNA.The results of agarosegel electrop horesis of NA19,NA1A,NA29 and topoisomerase Ⅰ showed that compound NA29had a strong inhibitory effect on topoisomerase Ⅰ activity.Further cycle arrest experiments showed that compounds NA1A,NA19 and NA29 mainly blocked HepG2 cells at G1 phase,and the concentration of compounds was positively correlated with G1 phase cells.When the compound concentration was 2μM,the G1-phase retardation rates were 69.18%,91.60%and 61.23%,respectively.This article provides a basis for further researchand is expected to find highly effective and low-toxic anti-tumor agents.