title: Synthesis and biological evaluation of hesperetin derivatives as agents inducing apoptosis.
abstract: A flavanone, hesperetin, has been known to exert antitumor activity by inducing apoptosis. To find hesperetin derivatives showing better antitumor activity, 12 derivatives were designed and synthesized. Their antitumor activities were measured using a long-term survival clonogenic assay. Among the compounds, K-5b, hesperetin-7-butyrate, showed the half-maximal cell growth inhibitory concentration three times as low as that of hesperetin. To compare the cytotoxicity of hesperetin and K-5b, the HCT116 human colon cancer cell line was treated with various concentrations of each compound. K-5b decreased the cell viability to a larger extent than hesperetin and triggered apoptosis more efficiently than hesperetin in an apoptosis detection assay using fluorescein isothiocyanate-labeled annexin V. Immunoblotting analysis showed that K-5b promoted caspase-mediated apoptosis more efficiently than hesperetin. Because hesperetin has been reported to induce apoptosis through the activation of the c-Jun N-terminal kinase (JNK) pathway, we tested whether K-5b activates JNKs. K-5b stimulated JNK1 and JNK2 more efficiently than hesperetin as shown by western blot analysis. In conclusion, hesperetin derivatives exerting better antitumor activity than hesperetin by inducing apoptosis were found.
authors.affiliation: Department of Biochemical Engineering, Gangneung-Wonju National University, Gangwondo 210-702, Republic of Korea.
authors.forename: Kang-Yeoun
authors.initials: KY
authors.lastname: Jung
authors.affiliation: Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Biochemical Engineering, Gangneung-Wonju National University, Gangwondo 210-702, Republic of Korea.
authors.forename: Young-Sung
authors.initials: YS
authors.lastname: Han
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 143-701, Republic of Korea. Electronic address: shinsy@konkuk.ac.kr.
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
authors.affiliation: Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701, Republic of Korea. Electronic address: yoongho@konkuk.ac.kr.
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003114:Colony-Forming Units Assay; D045325:HCT116 Cells; D006569:Hesperidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000625539:hesperetin-7-butyrate; D006569:Hesperidin; D000071137:Poly (ADP-Ribose) Polymerase-1; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; C013015:hesperetin
keywords: Apoptosis; Hesperetin; Hesperetin-7-butyrate; JNKs