@misc{10481/83692,
year = {2023},
url = {https://hdl.handle.net/10481/83692},
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.},
organization = {Consejería de Universidad, Investigación e Innovación of the Junta de Andalucía and FEDER, Una
manera de hacer Europa (P18-RT-1679, PT18-TP-4160, B-FQM-475-
UGR18 and PAIDI-TC-PVT-PSETC-2.0.)},
organization = {Research Results Transfer
Office (OTRI) of the University of Granada (PR/17/006),},
organization = {panish
Ministry of Economy and Competitiveness (PID2019.110987RB.I00 and
PID2021.128109OB.I0)},
organization = {Health Institute Carlos III (DTS18/
00121)},
organization = {EPSRC (EP/L000253/1)},
organization = {European Union’s Horizon 2020 Research and Innovation
Program under Marie Sklodowska-Curie Grant Agreement no. 754446},
organization = {HPC-Europa3 Transnational Access programme supported by the European
Commission H2020 Research & Innovation GA # 730897},
organization = {Funding for open access charge: Universidad de Granada / CBUA.},
publisher = {Elsevier},
keywords = {Hyaluronic acid},
keywords = {Cluster of differentiation 44},
keywords = {Tetrahydroisoquinoline},
keywords = {Molecular dynamics simulations},
keywords = {Antiproliferative effect},
keywords = {Three-dimensional cancer model evaluation},
title = {N-Aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: design, synthesis, computational studies, and antitumor effect},
doi = {10.1016/j.ejmech.2023.115570},
author = {Espejo Román, José Manuel and Rubio Ruiz, Belén and Chayah Ghaddab, Meriem and Sánchez Martín, Rosario María and Cruz López, Olga María and Conejo García, Ana},
}