Euodenine A: A Small-Molecule Agonist of Human TLR4

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Neve, Juliette E
Wijesekera, Hasanthi P
Duffy, Sandra
Jenkins, Ian D
Ripper, Justin A
Teague, Simon J
Campitelli, Marc
Garavelas, Agatha
Nikolakopoulos, George
Le, Phuc V
Leone, Priscila de A
Pham, Ngoc B
Shelton, Philip
Fraser, Neil
Carroll, Anthony R
Avery, Vicky M
McCrae, Christopher
Williams, Nicola
Quinn, Ronald J
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Gunda I. Georg and Shaomeng Wang

Date
2014
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Abstract

A small-molecule natural product, euodenine A (1), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor. SAR development around the cyclobutane ring resulted in a 10-fold increase in potency. The natural product demonstrated an extracellular site of action, which requires the extracellular domain of TLR4 to stimulate a NF-?B reporter response. 1 is a human-selective agonist that is CD14-independent, and it requires both TLR4 and MD-2 for full efficacy. Testing for immunomodulation in PBMC cells shows the induction of the cytokines IL-8, IL-10, TNF-a, and IL-12p40 as well as suppression of IL-5 from activated PBMCs, indicating that compounds like 1 could modulate the Th2 immune response without causing lung damage.

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Journal of Medicinal Chemistry

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57

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4

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Medicinal and biomolecular chemistry

Medicinal and biomolecular chemistry not elsewhere classified

Organic chemistry

Pharmacology and pharmaceutical sciences

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