Development of a Series of Tanshinone Derivatives Through Scaffold Hopping for Treating Non-Small-Cell Lung Cancer (NSCLC).

Non-small-cell lung cancer (NSCLC) is one of the most prevalent cancer types and accounts for the majority of cancer-related deaths worldwide. Tanshinone and its derivatives exhibit diverse biological activities, and their prominent antitumor potential has been well documented. In this study, we rationally designed a series of tanshinone derivatives with a scaffold-hopping strategy. Thirty-five tanshinone derivatives were synthesized, and their cytotoxic activities against the NSCLC cell lines A549 and H838 were investigated. Concurrently, their safety profile was assessed in BEAS-2B cells. The results showed that compounds S2-1, S2-4, and S2-8 exhibited superior inhibitory activity against A549 cells compared with the positive control, β-lapachone. Meanwhile, compounds S2-1, S2-3, S2-4, S2-8, S2-13, and S2-14 exhibited similar or increased antiproliferation activity against H838 cells. Compounds S2-4 (0.58 ± 0.07 μM) and S2-8 (0.42 ± 0.04 μM) demonstrated the greatest potency towards H838 cells; compounds S2-13 (1.28 ± 0.13 μM) and S2-14 (1.80 ± 0.24 μM) exhibited potent and selective activity towards H838 cells. Molecular docking studies of S2-4/NLRP3 and S2-14/STAT3, combined with the structure-activity relationship (SAR) analysis, indicated that the benzofuran core containing an ortho-quinone, along with an amide linkage and a 1,2,3-triazole group introduced at the C-2 position of the furan ring, is an effective chemical scaffold for enhancing the anti-NSCLC activity of tanshinone derivatives.