Thio-barbiturate-derived compounds are novel antioxidants to prevent LPS-induced inflammation in the liver
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Kyoung Mi Moon1,5,*, Bonggi Lee1,5,*, Ji Won Jeong1, Dae Hyun Kim1, Yun Jung Park2, Hye Rim Kim2, Ji Young Park2, Min Jo Kim1, Hye Jin An1, Eun Kyeong Lee1, Young Mi Ha3, Eunok Im1, Pusoon Chun4, Jin Yeul Ma5, Won-Kyung Cho5, Hyung Ryong Moon2 and Hae Young Chung1
1Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan, Korea
2Laboratory of Medicinal Chemistry, College of Pharmacy, Pusan National University, Busan, Republic of Korea
3Department of Chemistry, Dong-A University, Busan, Republic of Korea
4College of Pharmacy, Inje University, Inje-ro, Gyeongnam, Korea
5Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu, Republic of Korea
*These authors have contributed equally to this work
Hae Young Chung, email: [email protected]
Hyung Ryong Moon, email: [email protected]
Keywords: oxidative stress, antioxidant, compound 2d, compound 2l, inflammation
Received: May 24, 2017 Accepted: July 12, 2017 Published: October 10, 2017
Liver inflammation is closely associated with metabolic syndrome. Oxidative stress plays a synergistic role in inflammation by activating nuclear factor kappa B (NF-κB) signaling in the liver. Therefore, substantial efforts have been made to develop compounds that inhibit the generation of oxidative stress and activation of NF-κB. We synthesized twenty-six novel 5-(substituted benzyl)-2-oxo- and 5-(substituted benzyl)-2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione derivatives for the development of potential antioxidants and examined their biological activities in vitro and in vivo. Thio-barbiturate-derived compounds 5-[4-hydroxy-3-methoxybenzy]-2-thioxodihydropyrimidine-4,6[1H,5H]-dione (2d) and 5-[4-hydroxy-3,5-methoxybenzy]-2-thioxodihydropyrimidine-4,6[1H,5H]-dione (2l) had the strongest inhibitory effect on reactive oxygen species and peroxynitrite generation in vitro. Furthermore, oral administration of compounds 2d and 2l in mice notably suppressed lipopolysaccharide (LPS)-induced oxidative stress and NF-κB activation in the liver. Because macrophages play an essential role in liver inflammation, we investigated the effects of these compounds on inflammatory signaling in LPS-induced RAW264.7 macrophages. LPS-induced NF-κB activation and protein expression of cyclooxygenase 2 and inducible nitric oxide synthase were inhibited by pretreatment of these compounds in macrophages. In parallel with this finding, the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and AKT signalings, which are upstream activators of p65, were decreased by these compounds in macrophages. Our study suggests that compounds 2d and 2l inhibit oxidative stress and NF-кB-mediated inflammation, at least partially, through suppressing PTEN/AKT signaling. Therefore, these compounds may be useful as therapeutic agents for the amelioration of inflammatory diseases.
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