Quinoline–Glycomimetic Conjugates Reducing Lipogenesis and Lipid Accumulation in Hepatocytes

Abstract

Nonalcoholic fatty liver disease (NAFLD), which is characterized by excess accumulation of triglyceride in hepatocytes, is the major cause of chronic liver disease worldwide and no approved drug is available. The mechanistic target of rapamycin (mTOR) complexes has been implicated in promoting lipogenesis and fat accumulation in the liver, and thus, serve as attractive drug targets. The generation of non- or low cytotoxic mTOR inhibitors is required because existing cytotoxic mTOR inhibitors are not useful for NAFLD therapy. New compounds based on the privileged adenosine triphosphate (ATP) site binder quinoline scaffold conjugated to glucose and galactosamine derivatives, which have significantly low cytotoxicity, but strong mTORC1 inhibitory activity at low micromolar concentrations, have been synthesized. These compounds also effectively inhibit the rate of lipogenesis and lipid accumulation in cultured hepatocytes. This is the first report of glycomimetic-quinoline derivatives that reduce lipid load in hepatocytes.

Interaction of a Triantennary Quinoline Glycoconjugate with the Asialoglycoprotein Receptor

“…However no significant change was observed in the expression levels of p‐p70S6 K (Thr 389). The lesser mTOR inhibition of the triantennary quinoline glycoconjugate may be attributed to the lower potency of the acyclic quinoline core 12 without an appropriate C‐6 substitution that prevented a stronger binding at the ATP binding site of mTOR complex [19,26] . Thus the targeted delivery of ligands with potential mTOR inhibitory activity would necessitate an improved designing and is currently under investigation in our laboratory.…”

“…Click conjugation of 1 with glucose and galactosamine derivatives furnished glycoconjugates 2 and 3 that further showed an enhancement in their anti‐lipidemic activities with reduced cytotoxicities. The activities of these glycoconjugates were attributed to the reduction in the cleavage of cytosolic SREBP‐1a and reduced entry to the nucleus [19] …”

“… Structures of previously reported quinoline derived mTOR inhibitors 1 – 3 and triantennary galactose conjugated quinoline derivative 4 [19] …”

“…Given this background, we investigated whether multimeric galactose conjugation with known mTOR inhibitors could be a viable strategy towards their targeted delivery to hepatocytes. Our previously designed quinoline derivatives ( 1 – 3 , Figure 1) with moderate mTOR inhibitory activities and lesser cytotoxicity appear as significant starting points for the development of targeted mTOR inhibition [19] . Hence, we envisioned the designing of a triantennary Gal‐quinoline conjugate for rendering high ASGPR binding affinity together with mTOR inhibition [21] .…”

“…[18] Recently, we have reported the development of quinoline derivatives (1-3, Figure 1) that preferentially inhibited the mTORC1 pathway and modestly decreased the lipid accumulation in cultured hepatocytes at a lower micromolar concentration (~10 μM). [19] Click conjugation of 1 with glucose and galactosamine derivatives furnished glycoconjugates 2 and 3 that further showed an enhancement in their anti-lipidemic activities with reduced cytotoxicities. The activities of these glycoconjugates were attributed to the reduction in the cleavage of cytosolic SREBP-1a and reduced entry to the nucleus.…”