2. Academic Validation
  3. CD44-targeted N-benzyltetrahydroisoquinoline derivatives as anticancer agents with high tumor-to-normal cell selectivity

CD44-targeted N-benzyltetrahydroisoquinoline derivatives as anticancer agents with high tumor-to-normal cell selectivity

  • Eur J Med Chem. 2025 Nov 15:298:118039. doi: 10.1016/j.ejmech.2025.118039.
Soledad Romero-Tamudo 1,  M Dora Carrión 2,  Meriem Chayah 3,  Jose M Espejo-Román 4,  Carmen Domene 5,  Rosario M Sánchez-Martín 6,  Olga Cruz-López 7,  Ana Conejo-García 8
Affiliations

Affiliations

  • 1 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Campus Cartuja s/n, 18071, Granada, Spain; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Avda. Ilustración 114, 18016, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain. Electronic address: soledadromero@ugr.es.
  • 2 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Campus Cartuja s/n, 18071, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain. Electronic address: dcarrion@ugr.es.
  • 3 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Campus Cartuja s/n, 18071, Granada, Spain; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Avda. Ilustración 114, 18016, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain; Department of Chemistry, University of Bath, Claverton Down, BA2 7AY, Bath, United Kingdom. Electronic address: chayahm@ugr.es.
  • 4 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Campus Cartuja s/n, 18071, Granada, Spain; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Avda. Ilustración 114, 18016, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain. Electronic address: jmespejo@ugr.es.
  • 5 Department of Chemistry, University of Bath, Claverton Down, BA2 7AY, Bath, United Kingdom. Electronic address: mcdn20@bath.ac.uk.
  • 6 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Campus Cartuja s/n, 18071, Granada, Spain; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Avda. Ilustración 114, 18016, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain. Electronic address: rmsanchez@ugr.es.
  • 7 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Campus Cartuja s/n, 18071, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain. Electronic address: olgacl@ugr.es.
  • 8 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Campus Cartuja s/n, 18071, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012, Granada, Spain. Electronic address: aconejo@ugr.es.
PMID: 40779813 DOI: 10.1016/j.ejmech.2025.118039
Abstract

CD44, a cell surface glycoprotein, plays a crucial role in Cancer progression by enhancing cell proliferation and resistance to Apoptosis. Targeting CD44 with small molecules is a promising Cancer therapy strategy. Building on our previous work with the tetrahydroisoquinoline (THIQ) derivative SRT1, we designed and synthesized a series of analogues (SRT2-SRT10) to explore their Anticancer potential. Among these, the sulfonate esters SRT5 and SRT6 were the most promising in CD44+ MDA-MB-231 breast Cancer cells. They effectively inhibited the HA-CD44 interaction, as demonstrated by binding assays and cell viability studies. In addition, molecular dynamics simulations predict that these esters interact with the same key residues within the CD44-HABD domain as those involved in HA recognition. In CD44+ lung Cancer cell lines (A549 and NCI-H23), SRT1 exhibited the strongest antiproliferative activity (EC50 = 0.88 and 0.42 μM, respectively), while SRT5 and SRT6 also showed significant efficacy, particularly in NCI-H23 cells. Interestingly, only SRT1 induced Apoptosis, suggesting distinct mechanisms of cell death. Kinase profiling revealed that SRT5 and SRT6 inhibited CD44-associated kinases, particularly Src, contributing to their Anticancer effects. In contrast, SRT1 appeared to act through a kinase-independent pathway. All compounds displayed high selectivity for Cancer cells over non-tumoral lung cells. ADME predictions suggested favorable pharmacokinetic properties. Overall, our results underscore the potential of N-benzylTHIQ derivatives, as selective agents for targeted therapy of lung Cancer and support further in vivo validation and mechanistic investigations.

Keywords

Antiproliferative effect; Cluster of differentiation 44; Hyaluronic acid; Molecular dynamics simulations; Tetrahydroisoquinoline.

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