A class of Trp-Trp-AA-OBzl: Synthesis, in vitro anti-proliferation/in vivo anti-tumor evaluation, intercalation-mechanism investigation and 3D QSAR analysis

From the anti-tumor active N-tryptophanyl-β-carboline-3-carboxylic acid benzyl ester and β-carboline-3-carbonyltryptophan benzyl ester, a pharmacophore, Trp-Trp-OBzl, was drawn. Based on the DOCK scores amino acid residue was inserted into the C-terminus of Trp-Trp-OBzl and twenty Trp-Trp-AA-OBzls (AA = amino acid residues) were provided as DNA intercalators. On the in vitro and in vivo models seventeen Trp-Trp-AA-OBzls were anti-tumor active, and twelve Trp-Trp-AA-OBzls were more active than cytarabine. In acute toxicity assay Trp-Trp-AA-OBzls did not damage the immunologic function and had an LD50 of more than 500 mg/kg. The relationships of structure and activity were analyzed with 3D QSAR. The action mechanism studies revealed that the in vivo anti-tumor action of Trp-Trp-AA-OBzls was the result of DNA intercalation.

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► Trp-Trp-OBzl was explored to be a pharmacophore of DNA intercalators.
► Amino acid (AA) modification provided twenty novel Trp-Trp-AA-OBzls.
► Docking of them d(CGATCG)2 resulted in high DOCK scores.
► On mouse model they were more effective than cytarabine.
► Acute toxicity assay gave no immunotoxicity and an LD50 of more than 500 mg/kg.