Espejo-Román, Jose M.Rubio Ruiz, BelénChayah-Ghaddab, MeriemVega-Gutierrez, CarlosGarcía García, GraciaMuguruza-Montero, ArantzaDomene, CarmenSánchez-Martín, Rosario M.Cruz-López, OlgaConejo-García, Ana2024-02-222024-02-2220230223-5234https://hdl.handle.net/10641/4082Hyaluronic 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.engAtribución-NoComercial-SinDerivadas 3.0 Españahttp://creativecommons.org/licenses/by-nc-nd/3.0/es/Hyaluronic acidCluster of differentiation 44TetrahydroisoquinolineMolecular dynamics simulationsAntiproliferative effectThree-dimensional cancer model evaluationjournal articleopen access10.1016/j.ejmech.2023.115570