2. Academic Validation
  3. Design, synthesis and docking studies of new benzothiophene and benzothienopyran derivatives as topoisomerase I inhibitors with potential immunomodulatory action via cGAS-STING signaling pathway

Design, synthesis and docking studies of new benzothiophene and benzothienopyran derivatives as topoisomerase I inhibitors with potential immunomodulatory action via cGAS-STING signaling pathway

  • Bioorg Chem. 2026 Jun 15:174:109757. doi: 10.1016/j.bioorg.2026.109757.
Shimaa M Alhamaky 1,  Nadia A Khalil 2,  Marwa S A Hassan 2,  Nada Osama 3,  Nora M Aborehab 4,  Shaymaa G Ibrahim 5,  Mostafa A Abdelaziz 6
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Gamal Abd El-Nasir Street, Shibin Elkom, 32511 Menoufia, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia National University, Cairo-Alexandria Agriculture Road, Menoufia, Egypt.
  • 2 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 33 Kasr El-Aini Street, Cairo, Egypt.
  • 3 Biochemistry Department, Faculty of Pharmacy, Menoufia University, Gamal Abd El Nasr Street, Shibin Elkom 32511, Menoufia, Egypt.
  • 4 Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6 October City, 12451 Giza, Egypt. Electronic address: [email protected].
  • 5 Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Cairo City 11571, Mokattam, Egypt. Electronic address: [email protected].
  • 6 Department of Chemistry, College of Wooster, Wooster, OH 44691, USA. Electronic address: [email protected].
PMID: 41844052 DOI: 10.1016/j.bioorg.2026.109757
Abstract

Cancer remains a major global health challenge, and the development of new therapeutic agents is urgently needed to overcome poor selectivity and multi-drug resistance. Targeting DNA replication Enzymes such as Topoisomerase I (Topo I), which regulates DNA topology during replication and transcription, represents an effective chemotherapeutic strategy. This study aimed to design and synthesize new benzothiophene and benzothienopyran derivatives as potential Topo I inhibitors with additional immunomodulatory activity. Four series of derivatives including benzothiophene (2a-c) and benzo[4,5]thieno[3,2-b]pyran (3a-c, 4a-c, and 5a-c) were synthesized, characterized, and biologically evaluated. In vitro cytotoxicity screening against the NCI-60 Cancer cell panel demonstrated broad and potent activity, with several compounds showing 70 to >100% growth inhibition. The most active derivatives were further assessed in a five-dose NCI assay and a DNA relaxation assay for Topo I inhibition. Compounds 2c and 5c exhibited superior Topo I inhibition (IC50 = 17.69 ± 0.6 μM and 18.79 ± 0.64 μM, respectively) compared with topotecan (IC50 = 27.27 ± 0.93 μM) and showed higher selectivity toward Cancer cells over PCS-800-017 normal cells. Both compounds induced G0/G1 cell cycle arrest and Apoptosis in SR leukemia cells. Notably, compound 5c activated the cGAS-STING pathway and modulated apoptosis-related markers. Molecular docking studies rationalized the superior Topo I inhibitory potential of compound 5cvia forming strong interaction with the Topo I-DNA complex. Molecular dynamics (MD) simulation studies demonstrated remarkable positional stability of compound 5c with no significant structural perturbations in the Topo I active site. Additionally, drug-likeness and pharmacokinetic properties, predicted by SwissADME, indicated that 5c complies with Lipinski's and Veber's rules of oral bioavailability showing a bioavailability score of 0.55. These findings highlight compound 5c as a promising Topo I Inhibitor with mechanistically validated multimodal Anticancer activity, superior inhibitory potency compared with topotecan, and enhanced selectivity toward Cancer cells over normal CD8+ cells, supporting its potential for further Anticancer drug development.

Keywords

Anticancer agents; Apoptosis induction; Benzothienopyran; Benzothiophene; CD8(+) cells; Docking; IRF3; Leukemia SR cells; Topoisomerase I; cGAS–STING signaling pathway.

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