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

doi:10.1016/j.bmcl.2016.07.037

Bioorganic & Medicinal Chemistry Letters

Volume 26, Issue 17, 1 September 2016, Pages 4301-4309

https://doi.org/10.1016/j.bmcl.2016.07.037 Get rights and content

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 (196.35 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.

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Acknowledgments

This work was supported by the Priority Research Centers Program (NRF, 2009-0093824) and Cooperative Research Program for Agriculture Science & Technology Development (RDA, PJ01130302). SY Shin was supported by the KU Research Professor Program of Konkuk University.

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

Abstract

Graphical abstract

Section snippets

Acknowledgments

Bioorg. Med. Chem.

Nutr. Res.

Chem. Biol. Interact.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Drug Discovery Today

Nat. Protoc.

Der Chemica Sinica