Synthesis of Enantiostructured Triacylglycerol Prodrugs Constituting an Active Drug Located at Terminal sn -1 and sn -3 Positions of the Glycerol Backbone

• Published in: Molecules
• Main Authors: Lena Rós Jónsdottir, Gudmundur G. Haraldsson
• Format: Article in Journal/Newspaper
• Language: English
• Published: MDPI AG 2025
• Subjects: asymmetric synthesis; enantiostructured triacylglycerols; lipase; n-3 PUFAs; acylglycerol prodrugs; ( S )-ibuprofen; Organic chemistry; QD241-441; Antarc*; Antarctica
• Online Access: https://doi.org/10.3390/molecules30050991; https://doaj.org/article/77f8a3c0400a4bf79b374d7fad931d7e

The current paper reports the asymmetric synthesis of a focused library of enantiostructured triacylglycerols (TAGs) constituting a potent drug of the NSAID type (ibuprofen or naproxen) along with a pure bioactive n-3 polyunsaturated fatty acid (PUFA) intended as a novel type of prodrug. In this second category, a TAG prodrug of the terminal sn -1 or sn -3 position of the glycerol skeleton is acylated with a single saturated medium-chain fatty acid (C6, C8, C10, or C12), and another with the drug entity; the PUFA (EPA or DHA) is located in the sn -2 position. This was accomplished by a six-step chemoenzymatic approach, two of which were promoted by a lipase, starting from enantiopure ( R )- and ( S )-solketals. The highly regioselective immobilized Candida antarctica lipase (CAL-B) played a crucial role in the regiocontrol of the synthesis. The most challenging key step involved the incorporation of the drugs that were activated as oxime esters by the lipase exclusively in the terminal position of glycerol that is protected as a benzyl ether. All combinations, a total of 32 such prodrug TAGs, were prepared, isolated, and fully characterized, along with 24 acylglycerol intermediates, obtained in very-high-to-excellent yields in the majority of cases.