Design, synthesis and bioactivities of TAR RNA targeting β-carboline derivatives based on Tat–TAR interaction

Abstract A series of new β-carboline derivatives 3 – 14 bearing guanidinium group or amino group-terminated side chain targeting the TAR RNA were designed and synthesized. Molecular modeling studies indicated that the minimal interaction energy was obtained for compound 11 , which contained the optimal linker of three methylene groups and the terminal guanidinium group interacted with the three-base bulge of TAR element by hydrogen bonds, which were the main contributor to the stability of drug–TAR RNA complex. To evaluate the ability of compounds 3 – 14 to block Tat–TAR interaction, we established a rapid, sensitive quantitative bioassay based on transient cotransfection of a Tat expression vector and a long terminal repeat region–chloramphenicol acetyltransferase (LTR–CAT) reporter construct in eukaryotic cells, monitoring the influence of the compounds on CAT expression levels with ELISA. Compounds 11 and 12 were the most active compounds of all in inhibiting Tat–TAR interaction bearing the terminal guanidinium group, and the optimal linker of the three methylene groups. Both compounds also exhibited anti-HIV-1 activity in MT4 cells, and their LD 50 values of intraperitoneal acute toxicity for mice were 320.0 and 104.3 mg/kg, respectively. Furthermore, the results of capillary electrophoresis (CE) suggest that it is through targeting TAR RNA that this series of compounds block the Tat–TAR interaction.