Development of inhibitors for ubiquitin pathway has been suggested as a promising strategy to treat several types of cancers, which has been showcased by recent success of a series of novel anticancer drugs based on inhibition of ubiquitin pathways. Although the druggability of enzymes in ubiquitin pathways has been demonstrated, ubiquitin itself, the main agent of the pathway, has not been targeted. Whereas conventional enzyme inhibitors are used to silence the ubiquitination or reverse it, they cannot disrupt the binding activity of ubiquitin. Herein, we report that the scaffolds of sulfonated aryl diazo compounds, particularly Congo red, could disrupt the binding activity of ubiquitin, resulting in the activity equivalent to inhibition of ubiquitination. NMR mapping assay demonstrated that the chemical directly binds to the recognition site for ubiquitin processing enzymes on the surface of ubiquitin, and thereby blocks the binding of ubiquitin to its cognate receptors. As a proof of concept for the druggability of the ubiquitin molecule, we demonstrated that Congo red acted as an intracellular inhibitor of ubiquitin recognition and binding, which led to inhibition of ubiquitination, and thereby, could be used as a sensitizer for conventional anticancer drugs, doxorubicin.

The heterogeneity of glioblastoma and recurrence pose a major threat to the life of brain cancer patients. The failure of the current therapeutic regime in preventing its recurrence leads to a growing need for effective cancer treatments with lesser side effects. Previous studies have shown the potential of plants extract to synthesize silver nanoparticles (AgNPs) against U‐87 MG cell line. However, the need for optimum sized and effective nanoparticles is still not fulfilled. Hence, the current work aimed to utilize size controlled bioavailable AgNPs capped with Aloe barbadensis (aqueous extracts) and study their effectiveness against U‐87 MG cells. Two different concentrations of Aloe vera extract (ALE) viz. ALE1 and ALE2, were used. Their physiochemistry was characterized via UV–Vis, dynamic light scattering (DLS), FE‐SEM (50–60 nm diameter), and energy dispersive X‐ray (EDX). The observed zeta potentials were −8 and −16 mV for ALE1– and ALE2–AgNPs, respectively. This indicated that ALE2–AgNPs were more stable. Further, the anticancer potency of both ALE–AgNPs at 0, 24, and 48 h was evaluated. MTT‐assay revealed ALE2–AgNPs were more cytotoxic, significantly inhibiting the proliferation of U‐87 MG, indicating their dose‐dependent cytotoxicity. At an effective concentration of ALE2–AgNPs, (i.e., 10 µg/mL) viability of cancer cell line decreased significantly to 40% after 24 h of treatment. In apoptotic analysis pronounced elevation in early apoptotic cells was noted (5.1% and 9.9% for ALE1– and ALE2–AgNPs, respectively). The significant cytotoxicity and observed apoptosis induction shows ALE–AgNPs’s therapeutic potential against glioblastoma and aqueous extract shows its high biocompatibility, thus having significant probability to be translated in clinical settings.