Pursuing\nPolypharmacology: Benzothiopyranoindoles\nas G‑Quadruplex Stabilizers and Topoisomerase I Inhibitors\nfor Effective Anticancer Strategies

Here, we explored the benzothiopyranoindole scaffold\nto develop\nantiproliferative agents with a polypharmacological profile targeting\nboth G-quadruplex (G4)-structures and Topoisomerase (Topo) I enzyme.\nIn a preliminary optimization phase, compound <b>1</b> was selected\nfrom an in-house collection as a suitable lead for the rational development\nof a small library of analogs (<b>2</b>-<b>5</b>). When\nassayed in NIH’s NCI-60 Human Cancer Cell Line In Vitro Screen\nProgram, compound <b>1</b> and its demethylated analogue <b>2</b> showed significant antiproliferative/cytotoxic activity.\nFurthermore, results suggested for <b>1</b> and <b>2</b> a dual mechanism of action, effectively binding and stabilizing\nG4 structures, while inhibiting the relaxation activity of TopoI and\nII. Notably, these compounds displayed a certain selectivity toward\nTopoI. The polypharmacological profile of <b>1</b> and <b>2</b> was validated in a human colon carcinoma cell line, underscoring\ntheir potential as lead candidates for developing novel and efficacious\nanticancer agents.