title: A class of Trp-Trp-AA-OBzl: Synthesis, in vitro anti-proliferation/in vivo anti-tumor evaluation, intercalation-mechanism investigation and 3D QSAR analysis.
abstract: 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 LD(50) 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.
authors.affiliation: College of Pharmaceutical Sciences, Capital Medical University, No. 10, Beijing 100069, PR China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Zhang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Yang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.forename: Meiqing
authors.initials: M
authors.lastname: Zheng
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianhui
authors.initials: J
authors.lastname: Wu
authors.forename: Shiqi
authors.initials: S
authors.lastname: Peng
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002243:Carbolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D003561:Cytarabine / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004055:Differential Thermal Analysis; D004354:Drug Screening Assays, Antitumor; D004952:Esters / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D009929:Organ Size / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D002243:Carbolines; D004952:Esters; D007364:Intercalating Agents; D003561:Cytarabine; C049236:carboline-3-carboxylic acid; D004247:DNA