New N-Alkylketonetetrahydroisoquinoline derivatives exhibits antitumor effect by HA-CD44 interaction inhibition in MDA-MB-231 breast cancer Chayah Ghaddab, Meriem Espejo Román, José Manuel Erviti Marticorena, Laura Huertas Camarasa, Felipe José Domene, Carmen Sánchez Martín, Rosario María Conejo García, Ana Cruz López, Olga María Hyaluronic acid Cluster of differentiation 44 Tetrahydroisoquinoline This work was funded by the project PID2021.128109OB.I00 financed by MICIU/AEI/10.13039/501100011033, and the project P18-RT-1679 financed by the Consejería de Universidad, Investigación e Innovación of the Junta de Andalucía and by ERDF A way of making Europe. C.D. thanks HECBioSim, the UK High End Computing Consortium for Biomolecular Simulation (hecbiosim.ac.uk), which is supported by the EPSRC EP/L000253/1 for awarding computing time in Jade, the Joint Academic Data science Endeavour (JADE) service and Bede, two of the UK’s regional Tier 2 high-performance computing facilities. The support of the N8 Centre of Excellence for Computationally Intensive Research (N8 CIR) funded by the N8 research partnership is gratefully acknowledged. Molecular interactions at the cell surface, in particular between hyaluronic acid (HA) and the cluster of differentiation 44 (CD44) receptor, are crucial in several biological processes and diseases such as cancer. Thus, inhibition of the HA-CD44 interaction has become a promising therapeutic strategy. Etoposide was the only antitumor compound known to inhibit the binding of CD44 to HA, thereby disrupting key functions that drive malignancy. However, our recent research led to the development of N-alkyl and N-aryl THIQ derivatives, which represented a significant advancement in this field. Here, we further explore the structure–activity relationships of a series of newly designed N-alkylcarbonyl THIQ and study the structural parameters that define both the CD44 inhibitory and antiproliferative activities. Compounds 5d and 7d showed the most improvement of the antiproliferative activity compared to the N-alkylketone 1. Cell viability, competitive binding assays and molecular dynamics studies demonstrated effective inhibition of HA-CD44 binding by compounds 5d and 7d. This work not only expands the arsenal of potential therapeutic agents targeting HA-CD44 interactions but also highlights the potential for new treatments that could more effectively disrupt cancer progression. 2026-01-09T13:01:36Z 2026-01-09T13:01:36Z 2025-01-23 journal article M. Chayah et al. Bioorganic Chemistry 156 (2025) 108212. https://doi.org/10.1016/j.bioorg.2025.108212 https://hdl.handle.net/10481/109425 10.1016/j.bioorg.2025.108212 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier