Synthesis of cyclic peptide chitinase inhibitors: Natural products with chemotherapeutic potential

Many pathogenic organisms need to hydrolyse chitin, a homopolymer of ȕ(1,4)-linked N-acetyl-D-glucosamine, at key points in their life cycles. Chitin is the main structural component of insect exoskeletons, the cell walls of fungi, and is also found in the eggshells of parasitic nematodes. Molecules able to inhibit chitinase enzymes in these organisms have considerable potential as novel fungicides, insecticides, and nematocides. The recent discovery of the human acidic mammalian chitinase and its apparent role in infl ammatory disorders such as asthma has led to renewed interest in this fi eld, but the lack of readily available broad spectrum inhibitors has until now severely limited research in this area. We will describe new, effi cient and fl exible solid phase syntheses of two families of potent chitinase inhibitors, derived from the cyclic pentapeptide natural products, argifi n and argadin. [1,2] These permit assembly, cyclisation, and key side chain derivatisations to be performed entirely upon the solid phase. The unusual modifi ed Arg residues of both peptides are installed via an orthogonally protected Orn, thus avoiding side reactions observed on fi nal deprotection in previous combined solid phase/solution approaches. SAR data for designed analogues vs typical fungal and mammalian chitinases will be presented, along with recent data on the X-ray structure-led dissection of the argifi n scaffold. (3) This has allowed us to identify, synthesise and evaluate, minimal active fragments from argifi n which may serve as starting points for a new generation of drug-like, peptidomimetic inhibitors.