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 <b>1</b> was selected from an in-house collection as a suitable lead for the rational development of a small library of analogs (<b>2</b>-<b>5</b>). When assayed in NIH's NCI-60 Human Cancer Cell Line In Vitro Screen Program, compound <b>1</b> and its demethylated analogue <b>2</b> showed significant antiproliferative/cytotoxic activity. Furthermore, results suggested for <b>1</b> and <b>2</b> 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 <b>1</b> and <b>2</b> was validated in a human colon carcinoma cell line, underscoring their potential as lead candidates for developing novel and efficacious anticancer agents.
Authors
- Sabrina Taliani (ORCID: https://orcid.org/0000-0001-8675-939X)
- Lisa Dalla Via (ORCID: https://orcid.org/0000-0002-9828-9388)
- Simona Marzano (ORCID: https://orcid.org/0000-0002-6938-1687)
- Silvia Salerno (ORCID: https://orcid.org/0000-0002-6072-4698)
- Emma Baglini (ORCID: https://orcid.org/0000-0002-8378-4052)
- Elisabetta Barresi (ORCID: https://orcid.org/0000-0002-9814-7195)
- Mariafrancesca Hyeraci (ORCID: https://orcid.org/0000-0001-9376-5974)
- Sandro Cosconati (ORCID: https://orcid.org/0000-0002-8900-0968)
- Federico Da Settimo (ORCID: https://orcid.org/0000-0002-7897-7917)
- Erica Salvati (ORCID: https://orcid.org/0000-0002-3373-7442)
- Jussara Amato (ORCID: https://orcid.org/0000-0001-6096-3544)
- Michele Roggia (ORCID: https://orcid.org/0009-0009-3860-2502)
- Benito Natale
- Serena Concetta Rita Reina
Institutions
- University of Pisa (IT)
- University of Padua (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Istituto di Fisiologia Clinica (IT)
- Institute of Molecular Biology and Pathology (IT)
- National Research Council (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00313
- Citations
- 1
- Primary Topic
- DNA and Nucleic Acid Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- Università degli Studi di Napoli Federico II
- Università degli Studi di Padova
- Università di Pisa
- Ministero dell'Università e della Ricerca