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

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

  • ACS Med Chem Lett. 2024 Oct 2;15(11):1875-1883. doi: 10.1021/acsmedchemlett.4c00313.
Silvia Salerno 1 2,  Elisabetta Barresi 1 2,  Michele Roggia 3,  Benito Natale 3,  Simona Marzano 4,  Mariafrancesca Hyeraci 5,  Serena Concetta Rita Reina 6,  Emma Baglini 7,  Jussara Amato 4,  Erica Salvati 6,  Lisa Dalla Via 5,  Federico Da Settimo 1 2,  Sandro Cosconati 3,  Sabrina Taliani 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy.
  • 2 Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, Lungarno Pacinotti 43/44, 56126, Pisa, Italy.
  • 3 DiSTABiF, Università della Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy.
  • 4 Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
  • 5 Department of Pharmaceutical and Pharmacological Sciences, University of Padua via F. Marzolo 5, 35131 Padova, Italy.
  • 6 Institute of Molecular Biology and Pathology, National Research Council, Via degli Apuli 4, 00185 Rome, Italy.
  • 7 CNR IFC, Institute of Clinical Physiology, National Research Council of Italy, CNR Research Area, Via G. Moruzzi 1, Pisa 56124, Italy.
PMID: 39563818 DOI: 10.1021/acsmedchemlett.4c00313
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.

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