Addition of 2-(ethylamino)acetonitrile group to nitroxoline results in significantly improved anti-tumor activity in vitro and in vivo

Abstract

Lysosomal cysteine peptidase cathepsin B, involved in multiple processes associated with tumor progression, is validated as a target for anti-cancer therapy. Nitroxoline, a known antimicrobial agent, is a potent and selective inhibitor of cathepsin B, hence reducing tumor progression in vitro and in vivo. In order to further improve its anti-cancer properties we developed a number of derivatives using structure-based chemical synthesis. Of these, the 7-aminomethylated derivative (compound 17) exhibited significantly improved kinetic properties over nitroxoline, inhibiting cathepsin B endopeptidase activity selectively. In the present study, we have evaluated its anti-cancer properties. It was more effective than nitroxoline in reducing tumor cell invasion and migration, as determined in vitro on two-dimensional cell models and tumor spheroids, under either endpoint or real time conditions. Moreover, it exhibited improved action over nitroxoline in impairing tumor growth in vivo in LPB mouse fibrosarcoma tumors in C57Bl/6 mice. Taken together, the addition of a 2-(ethylamino)acetonitrile group to nitroxoline at position 7 significantly improves its pharmacological characteristics and its potential for use as an anti-cancer drug.

Nitroxoline induces cell apoptosis by inducing MDM2 degradation in small‐cell lung cancer

“…15 NXQ was also considered as a potent and selective inhibitor of cathepsin B, hence reducing glioma tumor progression in vitro and in vivo, and a number of derivatives of NXQ were developed by using structure-based chemical synthesis in order to further improve its antitumor properties. 16,17 In this study, NXQ was found to suppress SCLC cell survival and induce SCLC cell apoptosis (Figures 1 and 2). These above indicated that it was conceivable that the widely used antibacterial agent NXQ might be tried for SCLC treatment in clinic.…”

“…In cholangiocarcinoma cells, NXQ also exhibited anticancer activity by inducing FoxM1 inhibition . NXQ was also considered as a potent and selective inhibitor of cathepsin B, hence reducing glioma tumor progression in vitro and in vivo, and a number of derivatives of NXQ were developed by using structure‐based chemical synthesis in order to further improve its antitumor properties . In this study, NXQ was found to suppress SCLC cell survival and induce SCLC cell apoptosis (Figures and ).…”

Nitroxoline: repurposing its antimicrobial to antitumor application

“…tumor growth compared to the nitroxoline (Mitrović et al, 2017). Taken together these results show that the nitroxoline scaffold can be used as a starting point for the synthesis of novel compounds with improved pharmacological characteristics (Mitrović et al, 2017).…”

“…Nitroxoline derivatives were prepared with the aim of improving its activity against cathepsin B (Mirković et al, 2011;Sosič et al, 2013Sosič et al, , 2018Mitrović et al, 2017). Evaluation of new compounds with structural modifications on various positions of the nitroxoline scaffold revealed the structural requirements for cathepsin B inhibition (Mirković et al, 2011;Sosič et al, 2013Sosič et al, , 2018Mitrović et al, 2016Mitrović et al, , 2017. The nitro group at position 5 of nitroxoline was identified as essential for nitroxoline binding to cathepsin B, its absence resulting in loss of cathepsin B inhibition.…”

“…It exhibited an 8-fold increase in inhibition of cathepsin B endopeptidase activity over that of nitroxoline and was also selective for cathepsin B over cathepsins L and H (Sosič et al, 2013). The compound was, therefore, evaluated further for its antitumor activity (Sosič et al, 2013;Mitrović et al, 2017). It showed higher activity than did nitroxoline for inhibition of tumor cell invasion and migration in vitro on cell lines in both two-dimensional and three dimensional models as well as in in vivo on tumor mice model compound 17 showed improved inhibition of (Sosič et al, 2013), compound 48 (Bhat et al, 2012) and compound BDF-1253 (Chen et al, 2018).…”