The discovery of potent and selective N6-modified adenosine derivatives as effective chemotherapeutic agents to overcome p53-dependent drug resistance in cancer and HPIV-3/AdV5 respiratory tract infections.

Abstract

A library of N6-modified adenosine derivatives (compounds 7–36) was synthesized via a one-step reaction of 6-chloro- or 2-amino-6-chloro-(β-D-ribofuranosyl)-9H-purine with primary or secondary amines. The structures of selected compounds (14, 31, 34) were confirmed by single-crystal X-ray diffraction, revealing diverse crystal packing motifs and hydrogen-bonding networks. Biological evaluation demonstrated a broad range of cytotoxic activities across a panel of cancer and non-cancer cell lines, ranging from highly potent to non-toxic derivatives. Structure–activity relationship analysis revealed that the biological properties of the synthesized compounds were strongly influenced by the nature of the N6 substituent, with distinct structural features governing anticancer and antiviral activities. Several compounds (21, 22, 28, 30, and 32) markedly reduced cancer cell viability, with compound 28 exhibiting the highest potency across multiple solid tumor models. Importantly, compound 28 induced apoptosis, suppressed proliferation, and rapidly decreased cell viability in both HCT116 and HCT116 p53−/− colorectal carcinoma cells, indicating p53-independent activity. In contrast, cladribine displayed pronounced p53 dependence, promoting apoptosis primarily in p53-proficient cells and inducing a senescence-like phenotype rather than rapid cell death. Antiviral screening identified compounds 22, 25, and 35 as promising inhibitors of human parainfluenza virus type 3 (HPIV-3), whereas compound 12 exhibited the highest activity and selectivity against human adenovirus type 5 (AdV5). Collectively, these findings identify N6-modified adenosines as a promising class of compounds for developing anticancer agents with p53-independent activity and reveal several derivatives as attractive scaffolds for further optimization toward antiviral agents targeting respiratory viruses.