Suberitamides A-C, Aryl Alkaloids from a Pseudosuberites sp. Marine Sponge that Inhibit Cbl-b Ubiquitin Ligase Activity.

Chang-Kwon Kim,Donna Voeller,Dongdong Wang,Barry R O'Keefe,Josep Saurí,Brice A P Wilson,Stanley Lipkowitz,Kirk R Gustafson

doi:10.3390/md18110536

Chang-Kwon Kim, Donna Voeller + Show 6 more

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https://doi.org/10.3390/md18110536

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Abstract

Three new aryl alkaloids named suberitamides A–C (1–3), were isolated from an extract of the marine sponge Pseudosuberites sp. collected along the coast of North Carolina. Their planar structures were established by extensive nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. To assign the challenging relative configuration of the saturated five-membered ring in suberitamide A (1), a simple and efficient NMR protocol was applied that is based on the analysis of 2- and 3-bond 1H-13C spin-spin coupling constants using a PIP (pure in-phase) HSQMBC (heteronuclear single quantum multiple bond correlation) IPAP (in-phase and anti-phase) experiment. Suberitamides A (1) and B (2) inhibited Cbl-b, an E3 ubiquitin ligase that is an important modulator of immune cell function, with IC50 values of approximately 11 μM.

Highlights

The Casitas B-lineage lymphoma proto-oncogene b (Cbl-b) is a RING finger E3 ubiquitin ligase that has been identified as a negative regulator of T-cells, NK cells, B cells, and different types of myeloid cells [1,2,3,4]
All 2D nuclear magnetic resonance (NMR) experiments were acquired with nonuniform sampling (NUS) set to 50% or 25%
HMBC experiments were run with n JCH = 8.0, 3.5, or 2.0 Hz, and the LR-HSQMBC experiment was optimized for n JCH = 2.0 Hz

Summary

Introduction

The Casitas B-lineage lymphoma proto-oncogene b (Cbl-b) is a RING finger E3 ubiquitin ligase that has been identified as a negative regulator of T-cells, NK cells, B cells, and different types of myeloid cells [1,2,3,4]. It regulates innate immune responses and plays an important role in host defense toward pathogens [5]. Compounds that can inhibit the ubiquitin ligase activity of Cbl-b may provide lead structures for the development of immune-modulating therapeutic interventions. In conjunction with ongoing NCI (National Cancer Institute) anticancer natural product discovery efforts [8,9], the extract of a North Carolina collection of the marine sponge Pseudosuberites sp. was screened, and showed significant activity in an assay for inhibitors of Cbl-b ubiquitin ligase [10].

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