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Quinoline–Glycomimetic Conjugates Reducing Lipogenesis and Lipid Accumulation in Hepatocytes
Author(s) -
Palit Subhadeep,
Mukherjee Sanghamitra,
Niyogi Sougata,
Banerjee Anindyajit,
Patra Dipendu,
Chakraborty Amit,
Chakrabarti Saikat,
Chakrabarti Partha,
Dutta Sanjay
Publication year - 2018
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800271
Subject(s) - lipogenesis , mtorc1 , chemistry , nonalcoholic fatty liver disease , biochemistry , mechanistic target of rapamycin , ursodeoxycholic acid , pharmacology , lipid metabolism , galactosamine , steatosis , pi3k/akt/mtor pathway , biology , fatty liver , endocrinology , medicine , apoptosis , glucosamine , disease
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.