New N-Alkylketonetetrahydroisoquinoline derivatives exhibits antitumor effect by HA-CD44 interaction inhibition in MDA-MB-231 breast cancer

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.