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Pyrrolidine analogs of arylceramide HPA-12
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1  Department of Organic Chemistry, Institute of Organic Chemistry, Catalysis and Petrochemistry, Faculty of Chemical and Food Technology, Slovak University of Technology


At the beginning of the millennium, the (R,R)-HPA-12 was found to be the first antagonist of ceramide transporter CERT, which has been identified as a key factor for the ER-to-Golgi trafficking of ceramides. Ten years later, we have revised the stereochemistry of the most active HPA-12 diastereomer to (R,S) and developed synthesis of more potent alkyl substituted HPA-12 analogs. In the present study, based on the experience of our research group, the synthesis of the constrained pyrrolidine analogs of both (R,S)-HPA-12 and (R,R)-HPA-12 starting from substituted pyroglutamic acids easily accessible via our methodology will be demonstrated. The efficient synthesis of both target diastereoisomers of pyrrolidine HPA-12 analog included four key reactions. First was aza-Michael addition in tandem with CIAT - crystallisation induced asymmetric transformation, which yielded almost pure diastereomer and established an important stereogenic centre. Second reaction was stereoselective cyclisation, which also yielded almost pure diastereomer and introduced oxoproline structure in the molecule. Consequently, the target diastereomers were prepared by stereoselective reduction of oxo group and Mitsunobu inversion respectively. Configuration of stereogenic centre created by this reduction plays significant role in biological activity of pyrrolidine HPA-12 analogs and was confirmed by X-ray analysis. The samples of final derivatives were tested against inhibition of CERT protein. The results of the binding assays to the CERT protein will be discussed.

Keywords: HPA-12; CERT protein; pyroglutamic acid; CIAT; Mitsunobu inversion