Design,Synthesis And Antitumor Activity Of Heterocyclic Segment Modified "Naphthalimide-polyamine" Conjugates

At present,the incidence of cancer and the death rate are increasing,and people's lives are greatly threatened.Therefore,anti-tumor drugs that are low-toxic,highly effective,and targeted for the treatment of cancer are hot topics that scientists have studied today.Naphthalimide derivatives are typical DNA intercalators and topoisomerase inhibitors,and have good anti-tumor activity.Mitomycine derivatives such as Mitoxonylamine and Ninafite have entered Clinical trials were conducted at the experimental stage,but most of them were limited due to side effects such as myelosuppressionPolyamines are relatively simple aliphatic compounds composed of two or more amino groups and have various biological functions such as regulating the growth,development,reproduction,aging,immunity,and cancer of organisms.The combination of a compound known to have anti-tumor activity and polyamines can enhance its selectivity and reduce toxic side effects on normal cells of the body.Our group has been working on this in recent years,and has obtained a number of polyamine conjugates with a certain selectivity and good antitumor activity.Based on the study of naphthalimide-polyamine conjugates in the early stage of the laboratory,the principle of pharmacophore combination was used to introduce the active components of common drugs(phenylpyrazole,quinazoline)into the naphthalimide core.The morpholine,imidazopyridine,and 2-aminothiazole)were modified with polyamines in an attempt to enhance their antitumor activity and selectivity.In this paper,four series of naphthalimide derivatives modified by 34 heterocyclic moieties were obtained from different synthesis routes using fluorene as raw material.The structures were confirmed by1H NMR,13C NMR,MS and elemental analysis.In addition,an MTT assay was used to initially test the in vitro cytotoxicity test of target compounds against human colon cancer cells(HCT-116),human hepatoma cells(HepG2)and human breast cancer cells(MDA-MB-231).After preliminary screening,it was found that:(a)Naphthalimide derivatives(CCC-J7-CCC-J11)modified with triamines or tetraamines in the CCC-J series have good inhibitory effects on these three types of tumor cells;(b)In the CCC-K series,N,N-dimethylethylenediamine-modified CCC-K1 has a strong inhibitory effect on HCT-116,whereas N,N-dimethylpropanediamine-modified CCC-K2 has a strong inhibitory effect on MDA-MB-231;(c)Naphthalimide derivatives CCC-M8 and spermine-modified naphthalimide derivatives derivatized with nor-spermidine in CCC-M series The inhibitory effect of CCC-M9 on tumor cells was the strongest;(d)The high spermine-modified naphthalimide derivative CCC-S8 had a high inhibitory effect on triple negative breast cancer(IC50 value of 5.24).CCC-J7 and CCC-M8 have also been observed to have certain fluorescence properties in cells,which has the potential to become fluorescent probes.