Facile Synthesis of the CERT Inhibitor HPA‐12 and Some Novel Derivatives

Abstract

HPA-12 is an inhibitor of CERT-mediated non-vesicular transport of ceramide from the ER membranes to the Golgi apparatus. The inhibitor effectively blocks the synthesis of the membrane lipid sphingomyelin and may represent a novel drug prototype. Previous syntheses relied on non-commercial catalysts or specialized chemistries. Here we present a straightforward and effective method to synthesize HPA-12 from commercially available protected L-serinol in four steps. Some new analogues were synthesized and evaluated for their CERT-binding activity.

Chemistry and Biology of HPAs: A Family of Ceramide Trafficking Inhibitors

“…[21] AT R-FRET homogeneousphase assay was specifically developed, allowing complete determination of HPA-12 EC 50 . [23] These data corroborate our evaluation with the CERT START domain that showed, on the other hand, that the cyclohexyl analogue displays ap rotein binding comparable to that of HPA-12. Crystals tructures of as eries of (1R,3R)-HPAs with C13 to C16 acyl chains in complex with the CERT START domain were reported,i ndicating ar ecognition mode very similart ot hat of the naturalc argo lipid Cer.…”

“…Arenz and coworkers [23] Chem. HPA-12 stereoisomers Aza-Michael-based crystallization-induced asymmetric transformation EC 50 determination by TR-FRET binding assay by competition versus biotinylated-ceramide bound to STARTd omain of CERT [32] BerkeŠ,Ballereau, GØnisson and coworkers [21] Meta-orpara-substituents on phenyl ring Chelation-controlled reduction of N-protected bamino ketones Not evaluated Ramapanicker and co-workers [26] Long alkyl chain in meta-o rpara-position on aromatic ring Aza-Michael-based crystallization-induced asymmetric transformation followed by Sonogashira coupling and triple bond reduction EC 50 determination by TR-FRET binding assay by competition versus biotinylated-ceramide bound to the STARTd omain of CERT [32] Daïch, GØnisson, Berkeš and coworkers [33] Replacement of the phenyl ring by long alkyl chains Aza-Michael-based crystallization-induced asymmetric transformation followed by hydrodesulfurization of thiophene ring EC 50 determination by TR-FRET binding assay by competition versus biotinylated-ceramide bound to STARTd omain of CERT [32] Daïch, GØnisson, Berkeš and coworkers [33] Not evaluated …”

“…Synthesis of (1R,3S)-HPA-12 by Arenz: [23] Scheme11. Synthesis of (1R,3S)-HPA-12 by Arenz: [23] Scheme11.…”

“…This synthetic sequence (Scheme 9) features ad iastereoselectivet andem Corey-Link and intramolecular nucleophilic acyl substitution reaction as ak ey step. In 2014, Arenz and co-workers [23] reported the preparation of both (1R,3S)-and( 1 R,3R)-HPA-12 startingf rom commercially availablep rotected l-serinol (Scheme 10) inspired by the commons ynthetic route to sphingosine startingf rom Garner's aldehyde. The serinol 33 was converted into the nitrile 34 in at wo-step transformation.…”

Chelation controlled reduction of N-protected β-amino ketones toward the synthesis of HPA-12 and analogues

“…10 The revised structure was confirmed using X-ray crystallographic analysis by Kobayashi et al 11 Thus the revised structure of HPA-12 has a syn-orientation of the amino and hydroxyl groups and hence methodologies for its synthesis should rely on syn-stereoselective reduction of the corresponding oxo-amino compounds. Recent reports on the synthesis of the (1R,3S) derivative of HPA-12 include a tandem approach using (S)-Wynberg lactone by Snowden et al, 12 Ru-catalyzed asymmetric rearrangement of isoxazolidines reported by Kang et al, 13 and the synthesis of HPA-12 and its analogues from serinol by Arenz et al 14 …”