Synthesis and cytotoxic activities of β-carboline amino acid ester conjugates

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 20; pp. 6998 - 7010
• Main Authors: Zhao, Ming, Bi, Lanrong, Wang, Wei, Wang, Chao, Baudy-Floc’h, Michèle, Ju, Jingfang, Peng, Shiqi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.10.2006; Elsevier Science; Elsevier
• Subjects: Amino Acids - chemistry; Anti-cancer; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Beta-carboline; Binding Sites; Biological and medical sciences; Carbolines - chemical synthesis; Carbolines - chemistry; Carbolines - pharmacology; Cell Line, Tumor; Cell Membrane Permeability - drug effects; Cell Proliferation - drug effects; Chemical Sciences; Cytotoxicity; DNA - chemistry; DNA - drug effects; Drug Design; Drug Screening Assays, Antitumor; Esters - chemistry; General aspects; HeLa Cells; Humans; In Vitro Techniques; Medical sciences; Models, Molecular; Molecular Structure; Organic chemistry; Pharmacology. Drug treatments; Structure-Activity Relationship; Tumor Cells, Cultured; Beta-carboline; Cytotoxicity; Anti-cancer; Antineoplastic agent; Monolayer; Intercalating agent; Carcinoma; Liver; Uterine cervix; Modeling; Aminoester; Hepatocyte; Structure activity relation; Molecular model; Membrane; Mammary gland; Chemical synthesis; Tumor cell; Interaction energy; Human; Bioavailability; Permeability; In vitro; Hela cell line; In vivo; Carboline derivatives; Cell line; DNA; Conjugated compound; Pharmacokinetics; Thermodynamic properties
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.06.021

β-Carboline represents a class of compounds with potent anti-tumor activity by intercalating with DNA. To further enhance the cytotoxic potency and bioavailability of β-carboline, a series of novel β-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 β-carboline amino acid ester conjugates demonstrated improved cytotoxic activity compared to the parental β-carbolines. In particular, the Lys/Arg conjugates were the most potent analogs with an IC 50 value of 4 and 1 μM 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 β-carboline amino acid ester conjugates and identified the β-carboline Lys/Arg conjugates as promising lead compounds for further in vivo biological and molecular evaluation.