First Synthesis of Argadin: A Nanomolar Inhibitor of Family‐18 Chitinases

Abstract

The first synthesis of the cyclic peptide natural product, argadin is reported. Use of a solid-phase approach featuring sidechain resin attachment through histidine and a novel protecting group strategy allows rapid and efficient access to the argadin backbone, whereupon the unusual 3-amino-5-hydroxy-2-pyrrolidone moiety of the peptide is introduced by oxidative cyclisation of a homoserine residue. Argadin is shown to exist as a 5:1 mixture of diastereoisomers at the 5-

2‐Iodoxybenzoic Acid—A Simple Oxidant with a Dazzling Array of Potential Applications

“…[109][110][111][112][113][114][115] For example, Eggleston and co-workers employed an oxidative ring closure of this type in the final step of the total synthesis of the potent chitinase inhibitor argadin (72,Scheme 25). [143] Remarkably, the transformation of the cyclic peptide into the target compound was achieved selectively in the absence of any protecting-group manipulations.…”

2‐Iodoxybenzoesäure – ein einfaches Oxidationsmittel mit einer Vielfalt an Anwendungsmöglichkeiten

“…Oxidative Halbaminalbildung in der Totalsynthese von Argadin. [143] Schema 26. Selektive Oxidation von Dihydronaphtholen zu Naphtholen.…”

“…[109][110][111][112][113][114][115] Beispielsweise wurde ein oxidativer Ringschluss dieses Typs im letzten Schritt der Totalsynthese des potenten Chitinase-Inhibitors Argadin (72) von Eggleston et al eingesetzt (Schema 25). [143] Besonders bemerkenswert an diesem Beispiel ist die Tatsache, dass das cyclische Peptid ganz ohne Schutzgruppenoperationen selektiv in die Zielverbindung überführt werden kann.…”

Synthesis and Structure-based Dissection of Cyclic Peptide Chitinase Inhibitors: New Leads for Antifungal and Anti-Inflammatory Drugs

“…malaria, filariasis) has been linked with the activity of chitinases from such organisms, while the overexpression of endogeneous mammalian chitinases, notwithstanding the absence of chitin from mammalian physiology, is a significant feature in asthma and lipid storage disorders such as Gaucher's disease [1]. Selective inhibitors of these enzymes are of great interest as new drug leads or biochemical probes, and in this context, we recently reported the first syntheses of two cyclic peptide natural products, argifin [2] and argadin [3], that show nanomolar inhibition of a range of family 18 chitinases.…”