title: Colorectal anticancer activities of polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamides.
abstract: To develop potent chemotherapeutic agents for treating colorectal cancers, polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamide derivatives were designed. Twenty-two novel derivatives were synthesized and their cytotoxicities were measured using a clonogenic long-term survival assay. Of these derivatives, 3-(1-hydroxynaphthalen-2-yl)-N-(3-methoxyphenyl)-5-(4-methoxyphenyl)-pyrazoline-1-carbothioamide (NPC 15) exhibited the best half-maximal cell growth inhibitory concentrations (196.35nM). To explain its cytotoxicity, further biological experiments were performed. Treatment with NPC 15 inhibited cell cycle progression and triggered apoptosis through the caspase-mediated pathway. Its inhibitory effects on several kinases participating in the cell cycle were investigated using an in vitro kinase assay. Its half-maximal inhibitory concentrations for aurora kinases A and B were 105.03μM and 8.53μM, respectively. Further analysis showed that NPC 15 decreased phosphorylation of aurora kinases A, B, and C and phosphorylation of histone H3, a substrate of aurora kinases A and B. Its molecular binding mode for aurora kinase B was elucidated using in silico docking. In summary, polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamides could be potent chemotherapeutic agents.
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 143-701, Republic of Korea.
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.
authors.forename: Seunghyun
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Hyuk
authors.initials: H
authors.lastname: Yoon
authors.affiliation: Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Hyeryoung
authors.initials: H
authors.lastname: Jung
authors.affiliation: Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Yearam
authors.initials: Y
authors.lastname: Jung
authors.affiliation: Department of Applied Chemistry, Dongduk Women's University, Seoul 136-714, Republic of Korea.
authors.forename: Dongsoo
authors.initials: D
authors.lastname: Koh
authors.affiliation: Department of Biological Sciences, Konkuk University, Seoul 143-701, Republic of Korea. Electronic address: yhlee58@konkuk.ac.kr.
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
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: D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D006801:Humans; D062105:Molecular Docking Simulation; D009284:Naphthols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013854:Thioamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009284:Naphthols; D011720:Pyrazoles; D013854:Thioamides; C005366:naphthyl acetate; C049826:2-methoxyacetaldehyde; D000079:Acetaldehyde
keywords: Aurora kinase; Colorectal cancer; In silico docking; Pyrazoline-carbothioamide; QSAR