Agelasine Diterpenoids and Cbl-b Inhibitory Ageliferins from the Coralline Demosponge Astrosclera willeyana.

Wei Jiang,Unwoo Kang,Ekaterina Goncharova,Heidi Bokesch,Barry O’Keefe,Dongdong Wang,Kirk Gustafson,Emily Smith,Donna Voeller,Stanley Lipkowitz,Antony Wamiru,Brice Wilson

doi:10.3390/md19070361

Abstract

An extract of the coralline demosponge Astrosclera willeyana inhibited the ubiquitin ligase activity of the immunomodulatory protein Cbl-b. The bioassay-guided separation of the extract provided ten active compounds, including three new N-methyladenine-containing diterpenoids, agelasines W–Y (1–3), a new bromopyrrole alkaloid, N(1)-methylisoageliferin (4), and six known ageliferin derivatives (5–10). The structures of the new compounds were elucidated from their spectroscopic and spectrometric data, including IR, HRESIMS, and NMR, and by comparison with spectroscopic data in the literature. While all of the isolated compounds showed Cbl-b inhibitory activities, ageliferins (4–10) were the most potent metabolites, with IC50 values that ranged from 18 to 35 μM.

Highlights

Marine Science & Technology Institute, College of Environmental Science & Engineering, Molecular Targets Program, Center for Cancer Research, National Cancer Institute, National Institutes of
Astrosclera willeyana were collected in Tonga in November
Agelasines W–Y (1–3) have bicyclic terpenoid skeletons with a prenyl side chain that terminates with an N-methyladenine subunit

Summary

Introduction

Marine Science & Technology Institute, College of Environmental Science & Engineering, Molecular Targets Program, Center for Cancer Research, National Cancer Institute, National Institutes of. Basic Science Program, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702-1201, USA. Cbl-b is essential for the negative regulation of T-cell activation, and it reduces the immune response to cancer cells [2,3]. In line with this function, cells that lack the cblb gene rejected tumors in various models and were resistant to rechallenge with tumors after initial tumor rejection in a variety of tumor models [4,5,6,7]. As part of an ongoing effort to identify small molecule inhibitors of the Cbl-b function from natural products [8], an extract of the sponge Astrosclera willeyana was screened and showed a marked reduction of Cbl-b ligase activity

Methods

Discussion

Conclusion