: 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.
Pursuing Polypharmacology: Benzothiopyranoindoles as G-Quadruplex Stabilizers and Topoisomerase I Inhibitors for Effective Anticancer Strategies / Salerno, S.; Barresi, E.; Roggia, M.; Natale, B.; Marzano, S.; Hyeraci, M.; Reina, S. C. R.; Baglini, E.; Amato, J.; Salvati, E.; Dalla Via, L.; Da Settimo, F.; Cosconati, S.; Taliani, S.. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 15:11(2024), pp. 1875-1883. [10.1021/acsmedchemlett.4c00313]
Pursuing Polypharmacology: Benzothiopyranoindoles as G-Quadruplex Stabilizers and Topoisomerase I Inhibitors for Effective Anticancer Strategies
Marzano S.;Salvati E.;Cosconati S.;Taliani S.
2024
Abstract
: 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
