CD44-targeted N-benzyltetrahydroisoquinoline derivatives as anticancer agents with high tumor-to-normal cell selectivity

Abstract

CD44, a cell surface glycoprotein, plays a crucial role in cancer progression by enhancing cell proliferation and resistance to apoptosis. Targeting CD44 with small molecules is a promising cancer therapy strategy. Building on our previous work with the tetrahydroisoquinoline (THIQ) derivative SRT1, we designed and synthesized a series of analogues (SRT2-SRT10) to explore their anticancer potential. Among these, the sulfonate esters SRT5 and SRT6 were the most promising in CD44+ MDA-MB-231 breast cancer cells. They effectively inhibited the HACD44 interaction, as demonstrated by binding assays and cell viability studies. In addition, molecular dynamics simulations predict that these esters interact with the same key residues within the CD44-HABD domain as those involved in HA recognition. In CD44+ lung cancer cell lines (A549 and NCI–H23), SRT1 exhibited the strongest antiproliferative activity (EC50 = 0.88 and 0.42 μM, respectively), while SRT5 and SRT6 also showed significant efficacy, particularly in NCI–H23 cells. Interestingly, only SRT1 induced apoptosis, suggesting distinct mechanisms of cell death. Kinase profiling revealed that SRT5 and SRT6 inhibited CD44-associated kinases, particularly SRC, contributing to their anticancer effects. In contrast, SRT1 appeared to act through a kinase-independent pathway. All compounds displayed high selectivity for cancer cells over non-tumoral lung cells. ADME predictions suggested favorable pharmacokinetic properties. Overall, our results underscore the potential of N-benzylTHIQ derivatives, as selective agents for targeted therapy of lung cancer and support further in vivo validation and mechanistic investigations.