August 10, 2024 – Asymmetric synthesis of ENT-03, the predicted mammalian ortholog of the dog fish shark aminosterol trodusquemine (MSI-1436)

William A. Kinney a, D. Phillip Cox a, Stephen R. Jones b, Edward J. Hessler c, Harold A. Karnes c, Thomas L. Fevig c, Bradley D. Hewitt c, Ryan Sullivan d, Nai-Wen Tseng d, Edward Pasion d, Thomas Beale d, Thorsten Rosner e, Ian T. Crouch e, Stephen D’Ambrosio e, Peter Wade e, Hui Chen e, Qi Gao e, Andrew S. Thompson e, Miguel Muzzio f, Denise Barbut a, Michael A. Zasloff a

a : Metabolics Pharma, a subsidiary of Enterin Inc., Suite 3125, 2005 Market Street, Philadelphia 19103, United States
b : ASI Chemicals LLC, 1837 University Circle, Cheyney, PA 19319, United States
c : Bridge Organics, 311 W. Washington Street, Vicksburg, MI 49097, United States
d : Eurofins CDMO Alphora Inc., 2070 Hadwen Road, Mississauga, Ontario L5K 2C9, Canada
e : J-Star Research Inc., 3001 Hadley Road, South Plainfield, NJ 07080, United States
f : IIT Research Institute, Chicago, IL 60616, United States

Full publication can be found here.

ENT-03 was predicted to be the mammalian equivalent of trodusquemine, based on knowledge of the bile acids produced in mammals, such as 7-HOCA. The individual C-25 isomers of ENT-03 were prepared and both isomers were detected in neonatal mouse brain and liver. Trodusquemine and ENT-03 have both demonstrated dramatic effects in obesity and insulin resistance. (25S)-ENT-03 was selected for development for the treatment of diabetes and obesity. In this paper the first synthesis of this putative natural product is described. Starting with a stereo-defined steroidal intermediate 2, the semi-synthesis involves three stereoselective steps: Horner-Emmons olefination, hydrogenation, and reductive amination. Asymmetric hydrogenation using a ruthenium coordinated Mandyphos ligand was found to be effective in controlling the C25-stereochemistry of both isomers. The syntheses of the ENT-03 isomers and a deuterated reference standard facilitated identification and quantification of this natural product in mouse tissues, and exploration of its therapeutic potential.