Identification and Biological Evaluation of ( <scp>4</scp> <i>H</i> ‐Thieno[3,2‐ <i>b</i> ]indol‐3‐yl)methanol as a Tumoricidal Scaffold for an Antineoplastic Agent

Considerable effort has been put into developing YC-1 (lificiguat), an indazole derivative with dual targets including soluble guanylate cyclase (sGC) and hypoxia-inducible factor-1 (HIF-1), as new drug molecules with increased potency. Building on our previous findings, this structure-activity relationship study focused on the substitutability of 4H-furo[3,2-b]indole derivatives. (4H-thieno[3,2-b]indol-3-yl)methanol was identified as the chemical skeleton for developing tumoricidal compounds. Notably, the chemotypes exhibited selective cytotoxicity toward cancer cell lines without affecting normal human fibroblasts. Among these compounds, (5-((3-(hydroxymethyl)-4H-thieno[3,2-b]indol-4-yl)methyl)furan-2-yl)methanol (28i) emerged as the most promising candidate, demonstrating robust antiproliferative efficacy against A498 renal carcinoma cells, with an IC₅₀ value of 21.0 nM. Moreover, 28i induced significant apoptosis in A498 cells at a concentration of 50 nM, accompanied by cell cycle arrest in the G₂/M phase. Western blot analysis of apoptosis-related proteins indicated that 28i induces mitochondrial-mediated apoptosis. Molecular docking studies on YC-1, 4H-furo[3,2-b]indole derivative A, and 28i demonstrated that compound 28i exhibited the highest docking score and possesses high potential for inhibiting HIF-1 by targeting the ARNT-dependent pathway. The structural framework of (4H-thieno[3,2-b]indol-3-yl)methanol makes it a promising candidate for cancer therapy.