Synthesis And Bioactivities Of New 4-nitro-n-phthaloyl Amino Acid Substituted Coumarins

Objective:In this study, to evaluate the biological activities and structure-activity relationship of the title compounds, a series of 4-nitro-N-phthaloyl amino acid substituted coumarins was designed and synthesized using 7-hydroxycoumarin and its methyl derivatives as the parent structure.Methods:A series of methyl substituted 7-hydroxycoumarins was synthesized, commencing with 2,4-dihydroxybenzaldehyde, 3,5-dihydroxytoluene and ethyl(triphenylphosphoranylidene)acetate, through methylation, reduction, Vilsmeier–Haack and Wittig reaction. Moreover, 4 derivants of amino acids were prepared by the reactions4-nitro-phthalic anhydride with 4 amino acids, respectively. Finally, target compounds were obtained by the esterification reaction of coumarin derivatives with amino acid derivatives and their structures were confirmed by ESI-MS,1H-NMR and13C-NMR spectra. Furthermore, the in vitro antiplatelet and antitumor activities of the target compounds were evaluated.Results:In this paper, 20 novel compounds were synthesized and structurally analyzed.Besides, their biological activities were tested and showed that compounds 3d, 4a, 5c, 5a and 5d exhibited higher antiplatelet activity(IC50= 50±19, 108±15, 130±22, 115±14 and141±36 μM, respectively) than that of positive drug Ozagrel Sodium(IC50= 190±32 μM).The structure-activity relationship revealed that both of the sorts of amino acids and the sites methyl substituted on coumarin were affected antiplatelet activity significantly. Partial compounds has mild antitumor effect on EC and Si Ha cells, among which compound 1b exhibited highest antitumor activity(IC50= 24.60±4.61 μM) to EC cells. The structure-activity relationship revealed that the antitumor activity was declined, when coumarin was methyl substituted.Conclusions:In this study, the synthesized compounds, 4-nitro-N-phthaloyl amino acid substituted coumarins exhibited considerable antiplatelet activity and mild antitumor activity.Compound 3d, which displayed highest antiplatelet activity, may be a lead compound for further chemical optimization and development of antiplatelet agents.