Find in Library

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling is an attractive therapeutic target for tumor therapy. Herein, forty-eight novel meridianin derivatives were designed and synthesized, and their antitumor activity was evaluated in vitro both for activity optimization and structure–activity relationship (SAR) study. The results indicated that most derivatives exhibited significantly improved antitumor activity, especially for compound <b>6e</b>. The compound <b>6e</b> contains an isothiouronium linked by an alkyl chain consisting of six carbon atoms with IC₅₀ ranging from 1.11 to 2.80 μM on various cancer cell lines. Consistently, the <b>6e</b> dose dependently induced the apoptosis of A549 and DU145 cells, in which STAT3 is constitutively active. Western blotting assays indicated that the phosphorylation levels of JAK1, JAK2 and STAT3 were inhibited by <b>6e</b> at 5 μM without significant change in the total STAT3 level. Moreover, <b>6e</b> also suppressed the expression of STAT3 downstream genes, including c-Myc, Cyclin D1 and Bcl-XL at 10 μM. An additional in vivo study revealed that <b>6e</b> at the dose of 10 mg/kg could potently inhibit the DU145 xenograft tumor without obvious body weight loss. These results clearly indicate that <b>6e</b> could be a potential antitumor agent by targeting the JAK/STAT3 signaling pathway.