Identification and Biological Evaluation of (4H-Thieno[3,2-b]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.