Design, Synthesis, Computational and Biological Evaluation of Novel Structure Fragments Based on Lithocholic Acid (LCA)
Jiangling Peng,
Mingjie Fan,
Kelly X. Huang,
Lina A. Huang,
Yangmeng Wang,
Runkai Yin,
Hanyi Zhao,
Senlin Xu,
Hongzhi Li,
Alon Agua,
Jun Xie,
David A. Horne,
Fouad Kandeel,
Wendong Huang,
Junfeng Li
Affiliations
Jiangling Peng
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Mingjie Fan
Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Kelly X. Huang
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Lina A. Huang
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Yangmeng Wang
Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Runkai Yin
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Hanyi Zhao
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Senlin Xu
Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Hongzhi Li
Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Alon Agua
Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Jun Xie
Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
David A. Horne
Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Fouad Kandeel
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Wendong Huang
Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Junfeng Li
Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
The regulation of bile acid pathways has become a particularly promising therapeutic strategy for a variety of metabolic disorders, cancers, and diseases. However, the hydrophobicity of bile acids has been an obstacle to clinical efficacy due to off-target effects from rapid drug absorption. In this report, we explored a novel strategy to design new structure fragments based on lithocholic acid (LCA) with improved hydrophilicity by introducing a polar “oxygen atom” into the side chain of LCA, then (i) either retaining the carboxylic acid group or replacing the carboxylic acid group with (ii) a diol group or (iii) a vinyl group. These novel fragments were evaluated using luciferase-based reporter assays and the MTS assay. Compared to LCA, the result revealed that the two lead compounds 1a–1b were well tolerated in vitro, maintaining similar potency and efficacy to LCA. The MTS assay results indicated that cell viability was not affected by dose dependence (under 25 µM). Additionally, computational model analysis demonstrated that compounds 1a–1b formed more extensive hydrogen bond networks with Takeda G protein-coupled receptor 5 (TGR5) than LCA. This strategy displayed a potential approach to explore the development of novel endogenous bile acids fragments. Further evaluation on the biological activities of the two lead compounds is ongoing.
