A novel rhein-piperazine-sulfonamide derivative as a potential candidate for treatment of non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is one of leading cause of cancer-related mortality and morbidity. Due to challenges such as low early diagnosis rates and high drug resistance, novel anti-NSCLC agents were urgently needed. Rhein, a compound derived from Chinese rhubarb, had shown potential antitumor properties. Moreover, derivatives of rhein had gained attention for their potential in enhancing bioavailability and better anticancer efficacy. In this study, a novel rhein-piperazine-sulfonamide analogue compound D was synthesized and tested for potential anti-cancer activity. Compound D demonstrated the strong anti-cancer activities with IC 50 about 5.17 μM against A549 cells with minimal toxicity to normal cells. In vitro assays proved that compound D inhibited NSCLC cells proliferation, migration, then induced apoptosis. Western blot results showed a reduction in the phosphorylation of PI3K, AKT, and mTOR protein after treatment with compound D , indicating a possible mechanism. In an NSCLC xenograft mouse model, mPEG 2000 -PCL 2000 amphiphilic block copolymers, an FDA-approved biomaterials, were first used to assemble a micelle to encapsulate the compound D inside to enhance its solubility. Then, compound D-loaded micelles showed significant inhibition ability of tumor growth and therefore improving its in vivo efficacy. In conclusion, compound D demonstrated promising anti-cancer activity in treatment of NSCLC by targeting the PI3K-AKT-mTOR pathway, offering a potential candidate for NSCLC therapies. • Novel rhein-piperazine-sulfonamide compound D was designed and exhibited a strong inhibitory effect on A549 lung cancer cells. • Compound D inhibited the A549 cells proliferation via reducing mitochondrial membrane potential, inhibiting cancer cell migration and cloning, promoting apoptosis and blocking the cell cycle. • Further mechanism discovered that compound D may exert anticancer effects by affecting the PI3K/AKT/mTOR pathway. • When encapsulated into PEG 2000 -PCL 2000 micelle, the compound D showed strong anti-tumor activity on A549 bearing mice and demonstrated with little systemic toxicity. • The compound D is worthy for further investigation as an anti-cancer candidate in future work.