Mycophenolic Acid Derivatives with Immunosuppressive Activity from the Coral-Derived Fungus Penicillium bialowiezense.

Qing Zhang,Jianping Wang,Weiguang Sun,Beiye Yang,Hucheng Zhu,Mengting Liu,Shuang Lin,Yongbo Xue,Zhengxi Hu,Fengli Li,Yonghui Zhang

doi:10.3390/md16070230

Qing Zhang, Jianping Wang + Show 9 more

Open Access

https://doi.org/10.3390/md16070230

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Journal: Marine drugs	Publication Date: Jul 7, 2018
Citations: 16	License type: CC BY 4.0

Affiliation: Huazhong University of Science and Technology

Abstract

Mycophenolic acid (MPA) is a potent inosine-5′-monophosphate dehydrogenase (IMPDH) inhibitor for immunosuppressive chemotherapy. Most importantly, as the 2-morpholinoethyl ester prodrug of MPA, mycophenolate mofetil (MMF) is a well-known immunosuppressant used to prevent rejection in organ transplantations. Nevertheless, due to its frequently occurred side effects, searching for new therapeutic agents is ongoing. In our current work, by virtue of efficient bioassay-guided fractionation and purification, eleven mycophenolic acid derivatives, including five previously unreported metabolites (3–7) and six known compounds (1, 2, and 8–11), were obtained from the coral-derived fungus Penicillium bialowiezense. Their structures were elucidated by means of extensive spectroscopic analyses (including 1D and 2D NMR and HRESIMS data) and comparison of the NMR and other physical data with those reported in the literature in the case of the known compounds. All the isolates 1–11 were evaluated for the immunosuppressive activity, and 1–3 showed potent IMPDH2 inhibitory potency with IC50 values of 0.84–0.95 μM, which were comparable to that of MPA (the positive control), while 4–10 showed significant inhibitory potency with IC50 values of 3.27–24.68 μM. All the MPA derivatives showed promising immunosuppressive activity, endowing them as potential drug leads for organ transplantations and autoimmune related diseases.

Highlights

With great advantages of unique ecological environments, powerful gene clusters, and high yields of secondary metabolites, marine-derived fungi represent a gigantic and insufficiently untapped reservoir for the exploration of novel bioactive marine natural products (MNPs) [1,2,3]
To assess the biological activity of the mycophenolic acid (MPA) derivatives, we primarily evaluated their IMPDH2
To assess the biological activity of the MPA derivatives, we primarily evaluated their revealed that all these compounds could inhibit IMPDH2 with IC50 values ranging from 0.59 to 24.68

Summary

Introduction

With great advantages of unique ecological environments, powerful gene clusters, and high yields of secondary metabolites, marine-derived fungi represent a gigantic and insufficiently untapped reservoir for the exploration of novel bioactive marine natural products (MNPs) [1,2,3]. Since the first report of MPA in 1893 [5], the MPA and its derivatives have attracted much attention from phytochemists and pharmacologists because of their wide array of bioactivities, such as immunosuppressive, antitumor, antiviral, and RNA capping inhibitory properties [6]. The studies on MPA and its derivatives are the hotspot fields owing to their potentials to provide natural chemotypes for the discovery of new therapeutic agents; for instance, MPA is a.

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