Synthesis And Antitumor Activity Screening In Vitro Of Amino Acid Modified DNA Intercalators And Synthetic Method Of Lysine Analog

DNA is an indispensable substance in biological activities such as growth,development and reproduction as a carrier of genetic information in living organism,and it is closely related to the occurrence of tumors and various genetic diseases.In the process of development of antitumor drugs,DNA intercalator is an important research area as the target of DNA.DNA intercalators bind tightly to the double helix structure of DNA,then they alter the structure and functions of DNA,thereby block DNA replication and inhibit the growth of tumor cells.Therefore,designing a new DNA intercalator capable of the ability of efficiently binding to DNA is of great importance for the development of antitumor drugs.In this paper,we designed and synthesized two series of bis-naphthalene compounds.The second series of compounds can bind to DNA by means of thread intercalating mode.We determined the structure of these compounds by ~1H NMR.The binding mode of small molecule compounds to DNA was studied by viscosity titration.The antitumor activity of these compounds in vitro was also studied by MTT assay.We have synthesized two series of a total of 10 bis-naphthalene compounds 8a~d、10a~f,these two series of compounds are linked by two different diamine linkers:the first series is hexamethylenediamine;the second series is diamine linker which has naphthalene ring structure.The compounds in each series have similar structures,the only difference is that their structures are modified by different amino acid.By means of viscosity titration experiments,we investigated the interaction between compounds 8a~d、10a~f and DNA,and we found that all these compounds bind to DNA in intercalating binding mode,However,except that compound 8a bounds to DNA in a double-intercalation mode at a higher concentration,the remaining compounds bound to DNA in a single-intercalation mode.Then we studied the antitumor activity of these compounds in vitro by MTT assay.We found that the compound 8a had the best antitumor activity among these 10 compounds in vitro,which was consistent with the result of the viscosity titration experiment.However,in general,the antitumor activity of compound 8a~d、10a~f is not very good.The first series of compounds have higher antitumor activity in vitro than the second series of compounds.In addition,we designed and opened a new synthetic route for 2,3-diaminopropionic acid.We obtained the final compound 2,3-diaminopropionic acid methyl ester,starting from serine,in five steps and 33%overall yield including the protection of carboxyl group and amino group,mitsunobu reaction,and the deprotection of the two amino group.The method is suitable for large-scale production,the material is easily available,and the yield is high.