Loading…

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

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 wit...

Full description

Saved in:
Bibliographic Details
Published in:European journal of medicinal chemistry 2023-10, Vol.258, p.115570-115570, Article 115570
Main Authors: Espejo-Román, Jose M., Rubio-Ruiz, Belén, Chayah-Ghaddab, Meriem, Vega-Gutierrez, Carlos, García-García, Gracia, Muguruza-Montero, Arantza, Domene, Carmen, Sánchez-Martín, Rosario M., Cruz-López, Olga, Conejo-García, Ana
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. [Display omitted] •A series of N-Aryltetrahydroisoquinolines as potential HA-CD44 interaction inhibitors was designed and synthesized.•Compounds 2e, 5 and 6 significantly reduce HA binding in CD44+ MDA-MB-231 cancer cells.•Compound 5 showed an EC50 ≤ 1 μM against the CD44+ MDA-MB-231 cancer cells.•Compound 5 disrupted the integrity of MDA-MB-231 spheroids, leading to an increase in dead cells.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2023.115570