Colorectal anticancer activities of polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamides

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• 作者：Soon Young Shin^a ; Seunghyun Ahn^b ; Hyuk Yoon^b ; Hyeryoung Jung^b ; Yearam Jung^b ; Dongsoo Koh^c ; Young Han Lee^a ; ^{yhlee58@konkuk.ac.kr" class="auth_mail" title="E-mail the corresponding author} ; Yoongho Lim^b ; ^{yoongho@konkuk.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Pyrazoline-carbothioamide ; Colorectal cancer ; Aurora kinase ; In silico docking ; QSAR
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 September 2016
• 年：2016
• 卷：26
• 期：17
• 页码：4301-4309
• 全文大小：1738 K

文摘

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 (196.35 nM). 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 105.03 μM and 8.53 μM, 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.