Natural Polyketides Isolated from the Endophytic Fungus
                        Phomopsis sp. CAM212 with a Semisynthetic Derivative Downregulating
                    the ERK/IκBα Signaling Pathways

Jean-Bosco Jouda; Emmanuel Mfotie Njoya; Serge Alain Tanemossu Fobofou; Zong Yuan Zhou; Zhe Qiang; Céline Djama Mbazoa; Wolfgang Brandt; Guo-lin Zhang; Jean Wandji; Fei Wang

doi:10.1055/a-1212-2930

Planta Medica, Table of Contents

Planta Med 2020; 86(13/14): 1032-1042
DOI: 10.1055/a-1212-2930

Biological and Pharmacological Activity

Original Papers

Natural Polyketides Isolated from the Endophytic Fungus Phomopsis sp. CAM212 with a Semisynthetic Derivative Downregulating the ERK/IκBα Signaling Pathways

Jean-Bosco Jouda‡

¹Department of Chemical Engineering, School of Chemical Engineering and Mineral Industries, University of Ngaoundere, Ngaoundere, Cameroon

,

Emmanuel Mfotie Njoya‡

²Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China

³Department of Biochemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon

,

Serge Alain Tanemossu Fobofou

⁴Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Halle (Saale), Germany

⁵Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA

,

Zong Yuan Zhou

²Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China

,

Zhe Qiang

²Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China

,

Céline Djama Mbazoa

⁶Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon

,

Wolfgang Brandt

⁴Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Halle (Saale), Germany

,

Guo-lin Zhang

²Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China

,

Jean Wandji

⁶Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon

,

Fei Wang

²Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China

› Author Affiliations

Abstract

Three previously undescribed natural products, phomopsinin A – C (1 – 3), together with three known compounds, namely, cis-hydroxymellein (4), phomoxanthone A (5) and cytochalasin L-696,474 (6), were isolated from the solid culture of Phomopsis sp. CAM212, an endophytic fungus obtained from Garcinia xanthochymus. Their structures were determined on the basis of spectroscopic data, including IR, NMR, and MS. The absolute configurations of 1 and 2 were assigned by comparing their experimental and calculated ECD spectra. Acetylation of compound 1 yielded 1a, a new natural product derivative that was tested together with other isolated compounds on lipopolysaccharide-stimulated RAW 264.7 cells. Cytochalasin L-696,474 (6) was found to significantly inhibit nitric oxide production, but was highly cytotoxic to the treated cells, whereas compound 1 slightly inhibited nitric oxide production, which was not significantly different compared to lipopolysaccharide-treated cells. Remarkably, the acetylated derivative of 1, compound 1a, significantly inhibited nitric oxide production with an IC₅₀ value of 14.8 µM and no cytotoxic effect on treated cells, thereby showing the importance of the acetyl group in the anti-inflammatory activity of 1a. The study of the mechanism of action revealed that 1a decreases the expression of inducible nitric oxide synthase, cyclooxygenase 2, and proinflammatory cytokine IL-6 without an effect on IL-1β expression. Moreover, it was found that 1a exerts its anti-inflammatory activity in lipopolysaccharide-stimulated RAW 264.7 macrophage cells by downregulating the activation of ERK1/2 and by preventing the translocation of nuclear factor κB. Thus, derivatives of phomopsinin A (1), such as compound 1a, could provide new anti-inflammatory leads.

Key words

Garcinia xanthochymus - Phomopsis sp. - polyketides - phomopsinin - anti-inflammatory - cytokines - MAPKs - NF-κB

Full Text

References

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