Synthesis and biological evaluation of novel isoxazoloquinone derivatives as potent STAT3-targeting antipsoriasis agents

• Published in: Bioorganic chemistry 2024-10, Vol.151, p.107617, Article 107617
• Main Authors: Chen, Ling, Zhu, Shuaiwen, Xie, Yuanzhu, Wang, Liuliu, Gao, Jinlei, Luo, Tiao, Li, Jijia, Deng, Xu, Ma, Dayou, Liu, Suyou, Luo, Zhiyong
• Format: Article
• Language: English
• Subjects: Animals; Antipsoriasis; Dose-Response Relationship, Drug; Humans; Inhibitor; Isothiazoloquinone; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Isoxazoloquinone; Lapachol; Mice; Mice, Inbred BALB C; Molecular Structure; Naphthoquinones - chemical synthesis; Naphthoquinones - chemistry; Naphthoquinones - pharmacology; Psoriasis - drug therapy; STAT3; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107617

[Display omitted] •Thirty-five novel isoxazoloquinone derivatives were synthesized and most of them showed decent antipsoriatic activity in vitro.•B20 inhibited STAT3 signaling pathways by binding to the SH2 domain of STAT3.•B20 inhibited the production of STAT3-downstream pro-inflammatory factor IL-17A.•B20 showed remarkable antipsoriatic activity in a mice model. Psoriasis is a troublesome scaling skin disease with no high-effective medication available by far. Signal transducer and activator of transcription 3 (STAT3) has recently been revealed as a crucial player in the pathogenesis and progression of psoriasis and emerged as an intriguing antipsoriatic drug target. Naturally occurring lapachol and its quinone analogs had been discovered as effective STAT3 inhibitors, however, their antipsoriatic effects are not well investigated. Previously, we have reported a series of isothiazoloquinone lapachol derivatives. Here, the antipsoriastic potentials of these isothiazoloquinones were investigated and, in addition, 35 novel isoxazoloquinone derivatives were prepared and studied for their anti-psoriasis properties. Among them, the most potent antipsoriatic compound B20 determined by in vitro test on HaCaT cells could directly bind to STAT3, reduce STAT3 level and inhibit STAT3 nuclear translocation. In vivo studies showed that topical application of B20 could effectively alleviate IMQ-induced psoriasis in mice with no obvious side effects. In addition, B20 inhibited the production of interleukin 17 (IL-17A), a STAT3-downstream cytokine essential for the progression of psoriasis, both in vitro and in vivo. Thus, isoxazoloquinone B20 is a potent STAT3-targeting antipsoriatic agent worth of further investigation.