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

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 HA-CD44 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.