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

Journal article

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

Authors: Espejo-Román, JM; Rubio-Ruiz, B; Chayah-Ghaddab, M; Vega-Gutierrez, C; García-García, G

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: European Journal of Medicinal Chemistry
• Volume: 258
• Pages: 115570-115570
• Article number: 115570
• Publication date: 2023-06-26
• DOI: 10.1016/j.ejmech.2023.115570
• EISSN: 1768-3254
• ISSN: 0223-5234
• Language: English
• Keywords: Biochemistry; Small molecule; Cancer; Biology; CD44; Cancer research; In vitro; Angiogenesis; Hyaluronic acid; Chemistry; Genetics; Cancer cell