2. Academic Validation
  3. N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect

N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect

  • Eur J Med Chem. 2023 Oct 5;258:115570. doi: 10.1016/j.ejmech.2023.115570.
Jose M Espejo-Román 1,  Belén Rubio-Ruiz 2,  Meriem Chayah-Ghaddab 3,  Carlos Vega-Gutierrez 4,  Gracia García-García 5,  Arantza Muguruza-Montero 6,  Carmen Domene 7,  Rosario M Sánchez-Martín 8,  Olga Cruz-López 9,  Ana Conejo-García 10
Affiliations

Affiliations

  • 1 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, Campus Cartuja s/n, 18071, University of Granada, 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 de Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15, 18012, Granada, Spain. Electronic address: jmespejo@ugr.es.
  • 2 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, Campus Cartuja s/n, 18071, University of Granada, 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 de Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15, 18012, Granada, Spain. Electronic address: belenrubio@ugr.es.
  • 3 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, Campus Cartuja s/n, 18071, University of Granada, 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 de Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15, 18012, Granada, Spain. 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, Campus Cartuja s/n, 18071, University of Granada, Granada, Spain. Electronic address: carlosvg@unizar.es.
  • 5 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, Campus Cartuja s/n, 18071, University of Granada, Granada, Spain. Electronic address: graciagg3@gmail.com.
  • 6 Department of Chemistry, University of Bath, Claverton Down, BA2 7AY, Bath, United Kingdom. Electronic address: arantza.muguruza.montero@gmail.com.
  • 7 Department of Chemistry, University of Bath, Claverton Down, BA2 7AY, Bath, United Kingdom; Chemistry Research Laboratory, University of Oxford, Mansfield Road, OX1 3TA, Oxford, United Kingdom. Electronic address: mcdn20@bath.ac.uk.
  • 8 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, Campus Cartuja s/n, 18071, University of Granada, 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 de Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15, 18012, Granada, Spain. Electronic address: rmsanchez@ugr.es.
  • 9 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, Campus Cartuja s/n, 18071, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15, 18012, Granada, Spain. Electronic address: olgacl@ugr.es.
  • 10 Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, Campus Cartuja s/n, 18071, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15, 18012, Granada, Spain. Electronic address: aconejo@ugr.es.
PMID: 37413883 DOI: 10.1016/j.ejmech.2023.115570
Abstract

Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with Cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44+ Cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC50 value of 0.59 μM against MDA-MB-231 cells and is effective to disrupt the integrity of Cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in Cancer treatment.

Keywords

Antiproliferative effect; Cluster of differentiation 44; Hyaluronic acid; Molecular dynamics simulations; Tetrahydroisoquinoline; Three-dimensional cancer model evaluation.

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