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

Jose M Espejo-Román; Belén Rubio-Ruiz; Meriem Chayah-Ghaddab; Carlos Vega-Gutierrez; Gracia García-García; Arantza Muguruza-Montero; Carmen Domene; Rosario M Sánchez-Martín; Olga Cruz-López; Ana Conejo-García

doi:10.1016/j.ejmech.2023.115570

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. Epub 2023 Jun 26.

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.

MeSH terms

Hyaluronic Acid* / chemistry
Hyaluronic Acid* / pharmacology

Substances

Hyaluronic Acid