Discovery of thieno[3,2-c]pyran-based leads for liver, lung and glioma cancer: synthesis, docking-guided optimization and apoptotic profiling

Abstract

Thieno[3,2-c]pyran is a versatile heterocyclic framework recognised as a core scaffold in numerous synthetic anticancer agents and naturally occurring alkaloids exhibiting potent antitumor activity across various malignancies, including lung, liver, breast, and prostate cancers. In this study, we report the synthesis of a series of substituted thieno[3,2-c]pyran derivatives and their biological evaluation against human hepatocellular carcinoma (HepG2) and lung adenocarcinoma (A549) cell lines. The in vitro cytotoxicity assays revealed promising IC₅₀ values: 5a exhibited 13.65 ± 0.32 µM (HepG2) and 12.35 ± 0.30 µM (A549), while 5n showed 13.26 ± 0.32 µM (HepG2) and 12.36 ± 0.30 µM (A549). Apoptosis-induction studies confirmed the anticancer potential of these compounds. However, compound 5e works well against Glioma cancer with a promising IC₅₀ value of 26 µM (LN229). We have also performed the testing of selected compounds against the non-cancerous cell line HEK293 under the same conditions and concentration, and no cytotoxicity. Among the synthesized compounds, 5a and 5n demonstrated significant binding affinities in molecular docking studies, with docking scores of −8.834 and −8.994 kcal mol⁻¹ against liver cancer targets, and −7.925 and −7.871 kcal mol⁻¹ against lung cancer targets, respectively. To further confirm the EGFR inhibition, selected compounds were tested agaist EGFR overexpressed glioma cell line, and good cytotoxicity confirms the proposed pathway. These findings suggest that compounds 5a, 5e and 5n warrant further investigation as lead molecules for the development of targeted therapies for liver, glioma and lung cancers.