The vitamin E derivative α-amplexichromanol as anti-inflammatory lead inspired from traditional African medicine

K Neukirch; A Rossi; M Raasch; S Pace; D Séraphin; JJ Helesbeux; AS Mosig; F Roviezzo; P Richomme; O Werz; A Koeberle

doi:10.1055/s-0039-3400108

Planta Medica, Table of Contents

Planta Med 2019; 85(18): 1553
DOI: 10.1055/s-0039-3400108

Main Congress Poster

Poster Session 2

The vitamin E derivative α-amplexichromanol as anti-inflammatory lead inspired from traditional African medicine

Authors

K Neukirch

¹Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena,, 07743, Jena Germany
A Rossi

²Department of Pharmacy, School of Medicine, University of Naples Federico II,, 80131, Naples Italy
M Raasch

³Institute of Biochemistry II and Center for Sepsis Control and Care, University Hospital Jena,, 07747, Jena Germany
S Pace

¹Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena,, 07743, Jena Germany
D Séraphin

⁴Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire,, 49070, Beaucouzé France
JJ Helesbeux

⁴Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire,, 49070, Beaucouzé France
AS Mosig

³Institute of Biochemistry II and Center for Sepsis Control and Care, University Hospital Jena,, 07747, Jena Germany
F Roviezzo

²Department of Pharmacy, School of Medicine, University of Naples Federico II,, 80131, Naples Italy
P Richomme

⁴Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire,, 49070, Beaucouzé France
O Werz

¹Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena,, 07743, Jena Germany
A Koeberle

¹Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena,, 07743, Jena Germany

Abstract

Full Text

The nut seeds of Garcinia kola are traditionally used in African medicine and known for their anti-microbial, anti-oxidative and anti-inflammatory activities. Structural optimization of the anti-inflammatory ingredient and potent 5-lipoxygenase inhibitor garcinoic acid [1] yielded α-amplexichromanol (α-AC) which is a semi-synthetic analog of endogenous vitamin E metabolites that mediate immune functions of vitamin E [2]. α-AC possesses superior 5-lipoxygenase-inhibitory activity as compared to garcinoic acid and the bioactive vitamin E metabolite α-T-13ʹ-COOH. Here we show that α-AC limits inflammation in murine peritonitis and experimental asthma in vivo and address the compound’s expected higher metabolic stability using a liver-on-chip model. α-AC significantly reduced 5-lipoxygenase-derived leukotriene (LT)C₄ levels along with inflammatory cell infiltration and bronchial hyperreactivity. Lipid mediator profiles in plasma, lung and bronchia are comprehensively altered and α-AC was detected in lung up to six days after the last i.p. administration in contrast to α-T-13ʹ-COOH. While α-T-13ʹ-COOH is efficiently degraded by β-oxidation, α-AC is predominantly sulfated but not truncated. Our results indicate α-AC as a promising natural product-inspired lead that is orally active and seemingly metabolically more stable as compared to garcinoic acid and endogenous vitamin E metabolites.

References

References
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2 Pein H, Ville A, Pace S, Temml V, Garscha U, Raasch M, Alsabil K, Viault G, Dinh CP, Guilet D, Troisi F, Neukirch K, Konig S, Bilancia R, Waltenberger B, Stuppner H, Wallert M, Lorkowski S, Weinigel C, Rummler S, Birringer M, Roviezzo F, Sautebin L, Helesbeux JJ, Seraphin D, Mosig AS, Schuster D, Rossi A, Richomme P, Werz O, Koeberle A. Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. Nat Commun 2018; 9: 3834