title: Synthesis and cytotoxic activities of beta-carboline amino acid ester conjugates.
abstract: Beta-carboline represents a class of compounds with potent anti-tumor activity by intercalating with DNA. To further enhance the cytotoxic potency and bioavailability of beta-carboline, a series of novel beta-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were tested using a panel of human tumor cell lines. In addition, the membrane permeability of these compounds was evaluated in vitro using a Caco-2 cell monolayer model. The beta-carboline amino acid ester conjugates demonstrated improved cytotoxic activity compared to the parental beta-carbolines. In particular, the Lys/Arg conjugates were the most potent analogs with an IC(50) value of 4 and 1 microM against human cervical carcinoma cells. The low interaction energy of Arg conjugate based on molecular modeling may contribute to its enhanced cytotoxicity. Taken together, this study provided new insights into structure-activity relationships in the beta-carboline amino acid ester conjugates and identified the beta-carboline Lys/Arg conjugates as promising lead compounds for further in vivo biological and molecular evaluation.
authors.affiliation: College of Pharmaceutical Sciences, Capital University of Medical Sciences, Beijing, 100054, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Lanrong
authors.initials: L
authors.lastname: Bi
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Michèle
authors.initials: M
authors.lastname: Baudy-Floc'h
authors.forename: Jingfang
authors.initials: J
authors.lastname: Ju
authors.forename: Shiqi
authors.initials: S
authors.lastname: Peng
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004952:Esters / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D002243:Carbolines; D004952:Esters; D004247:DNA