A New 1,2-Naphthoquinone Derivative with Anti-lung Cancer Activity

• Published in: Chemical & pharmaceutical bulletin Vol. 70; no. 7; pp. 477 - 482
• Main Authors: Nakagawa, Riko, Tateishi, Hiroshi, Radwan, Mohamed O., Chinen, Takuma, Ciftci, Halilibrahim, Iwamaru, Kana, Baba, Nanami, Tominaga, Yuna, Koga, Ryoko, Toma, Tsugumasa, Inoue, Jun-ichiro, Umezawa, Kazuo, Fujita, Mikako, Otsuka, Masami
• Format: Journal Article
• Language: English
• Published: The Pharmaceutical Society of Japan 01.07.2022
• Subjects: 1,2-naphthoquinone; apoptosis; cytotoxicity; lung cancer cell; nuclear factor-κB (NF-κB); p38 mitogen-activated protein kinase (MAPK)
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c21-01087

1,2-Naphthoquinone (2-NQ) is a nucleophile acceptor that non-selectively makes covalent bonds with cysteine residues in various cellular proteins, and is also found in diesel exhaust, an air pollutant. This molecule has rarely been considered as a pharmacophore of bioactive compounds, in contrast to 1,4-naphthoquinone. We herein designed and synthesized a compound named N-(7,8-dioxo-7,8-dihydronaphthalen-1-yl)-2-methoxybenzamide (MBNQ), in which 2-NQ was hybridized with the nuclear factor-κB (NF-κB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) as a nucleophile acceptor. Although 50 µM MBNQ did not inhibit NF-κB signaling, 10 µM MBNQ induced cell death in the lung cancer cell line A549, which was insensitive to 2-NQ (10 µM). In contrast, MBNQ was less toxic in normal lung cells than 2-NQ. A mechanistic study showed that MBNQ mainly induced apoptosis, presumably via the activation of p38 mitogen-activated protein kinase (MAPK). Collectively, the present results demonstrate that the introduction of an appropriate substituent into 2-NQ constitutes a new biologically active entity, which will lead to the development of 2-NQ-based drugs.