Synthesis And Bioactivity Evaluation Of Benzo[cd]indol-2(1H)-ones Modified By Polyamine

Malignant neoplasm is still one of the most common diseases that threatens human health in the twenty-first century,so the development of antitumor drugs with good curative effect and low side effects remains to be a difficult problem for scientists to solve.Recent years,1,8-naphthaolactam derivatives' significant biological activity is gradually being excavated by scientists,and it is also a very important anti-tumor compound nucleus.The representative of the 1,8-Naphthaolactam derivatives is benzo[c,d]indole-2(H)-one,which has a three-membered ring structure and it can be used as a potent DNA intercalator.Polyamines are a kind of low molecular weight aliphatic compound widely found in the organisms,which regulate many physiological and pathological processes of human,such as growth,development,senescence,immunity,cancer,and so on.It is shown that the level of demand for polyamines in tumor cells is higher than normal cells,we envision the conjugation of antineoplastic agents with polyamines,so the conjugates can use the intracellular polyamine transport(PAT)systems to be delivered into tumor cells.This target-directed drug system,aiming to reduce the side effects of normal cells and improve the selectivity of the drug.Our group has been focused on the polyamines-drug conjugates for many years.It was shown that some novel polyamine conjugates had potent antitumor activity.Based on the previous research,we utilized 1,8-naphthaolactam as the start material,modified with polyamines on the naphthalene ring,and synthesized three series of 1,8-naphthaolactam-polyamine conjugates.These compounds are new and their structures are confirmed by 1H NMR>13C NMR?MS and elemental analysis.The anti-proliferation activity of these compounds was tested by MTT assay in vitro against some kind of tumor cells,including HepG2,Hela,and SMMC-7721 lines.The results showed that these derivatives exhibited significantly inhibitory activity to tumor cells.Higher inhibition was obtained when polyamines was directly linked to 1,8-naphthaolactam by methylene group.In particular,when the non-native triamine,homospermidine was linked,the conjugates(such as the compound B8)showed more potent activity than the others,However,it also exhibited toxic to the normal cells.