2. Academic Validation
  3. New N-Alkylketonetetrahydroisoquinoline derivatives exhibits antitumor effect by HA-CD44 interaction inhibition in MDA-MB-231 breast cancer

New N-Alkylketonetetrahydroisoquinoline derivatives exhibits antitumor effect by HA-CD44 interaction inhibition in MDA-MB-231 breast cancer

  • Bioorg Chem. 2025 Mar:156:108212. doi: 10.1016/j.bioorg.2025.108212.
Meriem Chayah 1,  Jose M Espejo-Román 2,  Laura Erviti-Marticorena 3,  Felipe Huertas-Camarasa 4,  Carmen Domene 5,  Rosario M Sánchez-Martín 6,  Ana Conejo-García 7,  Olga Cruz-López 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; Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15 18012 Granada, Spain. Electronic address: chayahm@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; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Avda. Ilustración 114 18016 Granada, Spain; Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15 18012 Granada, Spain. Electronic address: jmespejo@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. Electronic address: lerviti99@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. Electronic address: felipehc@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; Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15 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; Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15 18012 Granada, Spain. Electronic address: aconejo@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; Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15 18012 Granada, Spain. Electronic address: olgacl@ugr.es.
PMID: 39884223 DOI: 10.1016/j.bioorg.2025.108212
Abstract

Molecular interactions at the cell surface, in particular between hyaluronic acid (HA) and the cluster of differentiation 44 (CD44) receptor, are crucial in several biological processes and diseases such as Cancer. Thus, inhibition of the HA-CD44 interaction has become a promising therapeutic strategy. Etoposide was the only antitumor compound known to inhibit the binding of CD44 to HA, thereby disrupting key functions that drive malignancy. However, our recent research led to the development of N-alkyl and N-aryl THIQ derivatives, which represented a significant advancement in this field. Here, we further explore the structure-activity relationships of a series of newly designed N-alkylcarbonyl THIQ and study the structural parameters that define both the CD44 inhibitory and antiproliferative activities. Compounds 5d and 7d showed the most improvement of the antiproliferative activity compared to the N-alkylketone 1. Cell viability, competitive binding assays and molecular dynamics studies demonstrated effective inhibition of HA-CD44 binding by compounds 5d and 7d. This work not only expands the arsenal of potential therapeutic agents targeting HA-CD44 interactions but also highlights the potential for new treatments that could more effectively disrupt Cancer progression.

Keywords

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

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