Bioconjugate Chemistry 2011-04-20

Chemical and enzyme-assisted syntheses of norbuprenorphine-3-β-D-glucuronide.

Jinda Fan, Sarah M Brown, Zhude Tu, Evan D Kharasch

Index: Bioconjug. Chem. 22(4) , 752-8, (2011)

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Abstract

Norbuprenorphine-3-β-d-glucuronide (nBPN-3-β-d-G, 1) is a major phase II metabolite of buprenorphine, a pharmaceutical used for the treatment of opioid addiction. The pharmacological activity of compound 1 is not clear because investigations have been limited by the lack of chemically pure, well characterized 1 in sufficient quantities for in vitro and in vivo experiments. This work describes two concise, new methods of synthesis of 1, a chemical and an enzyme-assisted synthesis. The chemical synthesis used a strategy based on a combination of Koenig-Knorr coupling and amino-silyl protection. The enzyme-assisted synthesis used dog liver to convert the substrate norbuprenorphine (nBPN, 2) to 1. Both methods provided 1, characterized by (1)H NMR and tandem mass spectrometry, with purity >96%. The fractional yield of the enzyme-assisted synthesis was greater than that of the chemical synthesis (67% vs 5.3%), but due to larger reaction volumes, the chemical synthesis afforded greater amounts of total 1.