Recent animal studies indicating that lipoic acid (LA) may help lower abnormally high blood lipid levels, a risk factor for heart disease, have sparked interest into the biological mechanism of action of LA. The long term goal of this interdisciplinary research is the identification of the cellular proteins that interact with LA and its reduced form, dihydrolipoic acid (DHLA), through disulfide-dithiol exchange. To serve as cell impermeable biochemical tools, monolipoate polyethylene glycol 4000 (PEG) conjugates of both LA and DHLA were synthesized. The couplings of LA to lower molecular weight PEG molecule using carbodiimide chemistry has been reported. However, there are no reports describing esterification of LA to PEG 4000, and the size and polarity of this scaffold necessitated a modification of the methods applied for synthesis, purification, and characterization of the conjugate. Synthesis of the monolipoate LA conjugate was accomplished in two steps. Conversion of LA to a reactive acid chloride was followed by esterification with PEG 4000 to give a mixture of mono PEG 4000 lipioate ester and dilipoate ester. Selective precipitation based on solubility differences of the products, followed by reverse phase column chromatography yielded the desired monolipoate product. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy, infrared spectroscopy and high performance liquid chromatography were used in characterization of the monolipoated product. The monolipoate product was used as starting material for the synthesis of the PEG DHLA conjugate. Reduction of the disulfide bond in the monolipoate was carried out using tris(2-carboxyethyl)phosphine hydrochloride yielding the mono-(dihydrolipoate) ester. Ellman's reagent (DTNB) was used to qualitatively and quantitatively assay the DHLA product.

Novel synthesis of lipoic acid derivatives for biosynthetic pathways

247th National Meeting (2014)

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