Pursuing Polypharmacology: Benzothiopyranoindoles as G-Quadruplex Stabilizers and Topoisomerase I Inhibitors for Effective Anticancer Strategies.

Here, we explored the benzothiopyranoindole scaffold to develop antiproliferative agents with a polypharmacological profile targeting both G-quadruplex (G4)-structures and Topoisomerase (Topo) I enzyme. In a preliminary optimization phase, compound 1 was selected from an in-house collection as a suitable lead for the rational development of a small library of analogs (2-5). When assayed in NIH's NCI-60 Human Cancer Cell Line In Vitro Screen Program, compound 1 and its demethylated analogue 2 showed significant antiproliferative/cytotoxic activity. Furthermore, results suggested for 1 and 2 a dual mechanism of action, effectively binding and stabilizing G4 structures, while inhibiting the relaxation activity of TopoI and II. Notably, these compounds displayed a certain selectivity toward TopoI. The polypharmacological profile of 1 and 2 was validated in a human colon carcinoma cell line, underscoring their potential as lead candidates for developing novel and efficacious anticancer agents.