N-Aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: design, synthesis, computational studies, and antitumor effect Espejo Román, José Manuel Rubio Ruiz, Belén Chayah Ghaddab, Meriem Sánchez Martín, Rosario María Cruz López, Olga María Conejo García, Ana Hyaluronic acid Cluster of differentiation 44 Tetrahydroisoquinoline Molecular dynamics simulations Antiproliferative effect Three-dimensional cancer model evaluation Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejmech.2023.115570. Funding This research was funded by the Consejería de Universidad, Inves- tigaci´on e Innovaci´on 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.), the Research Results Transfer Office (OTRI) of the University of Granada (PR/17/006), the Spanish Ministry of Economy and Competitiveness (PID2019.110987RB.I00 and PID2021.128109OB.I00) and the Health Institute Carlos III (DTS18/ 00121). C.D. thanks HECBioSim, the UK High End Computing Con- sortium for Biomolecular Simulation (hecbiosim.ac.uk), which is sup- ported by the EPSRC (EP/L000253/1) for awarding computing time in Jade, a UK Tier-2 resource. B.R.-R. gratefully acknowledges funding from the European Union’s Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446 and UGR Research and Knowledge Transfer Fund—Athenea3i. J.M.E.-R. thanks the Spanish Ministry of Education for a studentship (FPU 16/ 02061). A.M.-M. gratefully acknowledges funding from the HPC- Europa3 Transnational Access programme supported by the European Commission H2020 Research & Innovation GA # 730897 (application number HPC17ARM6V). Funding for open access charge: Universidad de Granada / CBUA. 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. 2023-07-13T11:26:21Z 2023-07-13T11:26:21Z 2023 journal article J.M. Espejo-Román et al. N-Aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: design, synthesis, computational studies, and antitumor effect. European Journal of Medicinal Chemistry 258 (2023) 115570 [https://doi.org/10.1016/j.ejmech.2023.115570] https://hdl.handle.net/10481/83692 10.1016/j.ejmech.2023.115570 eng info:eu-repo/grantAgreement/EC/H2020/Marie Sklodowska-Curie Grant Agreement no. 754446 info:eu-repo/grantAgreement/EC/H2020/730897 http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier