Unraveling the potential for the novel agent, VR23, and its use as an anti-inflammatory for both acute and chronic inflammatory conditions

Abstract

Inflammatory conditions continue to be on the rise in Canada, due in part to the increase in aging population. Although effective in some cases, the anti-inflammatory drugs that are currently available have their own pitfalls, with toxic side effects and being non-selective in their mechanisms of action. In an attempt to develop an effective anti-inflammatory drug, I have characterized VR23, a novel 4-aminoquinoline derived sulfonyl hybrid compound. VR23 was initially developed in our laboratory as potentially an effective and safe anticancer agent. Previously, data obtained from an in vivo study for its anticancer effects raised a possibility that VR23 might also possess anti-inflammatory property. In a nutshell, data presented in this thesis confirm that the hypothesis is correct. In the study, I used both acute and chronic inflammatory models. In Chapter 1, I have shown that VR23 is able to effectively down-regulate proinflammatory cytokines comparably to dexamethasone, a well-known anti-inflammatory agent. Specifically, VR23 was able to down-regulate IL-6 with great sensitivity. In rheumatoid arthritis cell models of chronic inflammation, VR23 demonstrated superiority over the anti-rheumatic hydroxychloroquine in its ability to regulate pro-inflammatory cytokines. In Chapter 2, I demonstrated VR23’s anti-inflammatory mechanism is likely through its prevention of the phosphorylation of STAT3, leading to a decrease in the production of its down-stream targets, IL-6 and MCP-1. Lastly, in Chapter 3 I describe the discovery that VR23 is rapidly metabolized into CPQ and DK23. CPQ is not an active compound with respect to its anti-inflammatory activity, indicating that it is a by-product of the VR23 detoxification process. On the contrary, DK23 possesses active anti-inflammatory property, as potent as VR23 at their respective IC50 concentrations. Data from an acute lung injury model showed that the anti-inflammatory activity of VR23 is comparable to that of dexamethasone, a well-known corticosteroid. Data obtained from the rheumatoid arthritis study showed that VR23 is much more superior to hydroxychloroquine, a commonly used anti-rheumatic drug. Overall, this study demonstrates the potential for the novel compound, VR23, to be used as a non-toxic specific anti-inflammatory drug to treat IL-6 driven conditions such as rheumatoid arthritis.