Nitrilase mediated mild hydrolysis of a carbon ‐14 nitrile for the radiosynthesis of 4‐(7‐hydroxycarbamoyl‐[1‐14C‐heptanoyl]‐oxy)‐benzoic acid methyl ester, [14C]‐SHP‐141: A novel class I/II histone deacetylase (HDAC) inhibitor

SHP-141 (Remetinostat) is a drug candidate in Phase 1 development for the treatment of inflammatory and hyper-proliferative diseases of the skin. This drug was labelled with a single carbon-14 in four radiochemical steps and 45% yield to give[14C]-SHP-141 with a radiochemical purity of 90% and a specific activity of 190  μCi/mg. Key to the synthesis was the application of nitrilase biocatalysis, resulting in a mild and chemoselective hydrolysis. A strategy has been developed for the carbon-14 radiosynthesis of[14C]-SHP-141, a 4-(7-hydroxycarbamoyl-heptanoyloxy)-benzoic acid methyl ester derivative containing a terminal hydroxamic acid. The synthesis involved four radiochemical transformations. The key step in the radiosynthesis was the conversion of the 7-[14C]-cyano-heptanoic acid benzyloxyamide[14C]-4 directly into the carboxylic acid derivative, 7-benzyloxycarbamoyl-[14C]-heptanoic acid[14C]-8 using nitrilase-113 biocatalyst. The final step involved deprotection of the benzyloxy group using catalytic hydrogenation to facilitate the release of the hydroxamic acid without cleaving the phenoxy ester.[14C]-SHP-141 was isolated with a radiochemical purity of 90% and a specific activity of 190  μCi/mg from four radiochemical steps starting from potassium [14C]-cyanide in a radiochemical yield of 45%.

Source: Journal of Labelled Compounds and Radiopharmaceuticals - May 15, 2023 Category: Biochemistry Authors: Sean L. Kitson, William Watters, Thomas S. Moody, Todd Chappell, Ralph Mazitschek Tags: RESEARCH ARTICLE Source Type: research