Chitin is a glycopolymer consisting of +-(1, 4)-linked N-acetyl-D-glucosamine residues that occurs widely in nature and is a constituent of many organisms that are pathogenic to humans, including insects, fungi, and parasitic nematodes. As these organisms depend on the ability to break down chitin at key points of their life-cycle, inhibitors of the enzymes termed chitinases that catalyse the hydrolysis of chitin, are of considerable interest as potential drugs and insecticides. Although chitin is absent from mammalian physiology, two human chitinases along with several chitin-binding proteins (chi-lectins) have been associated with the onset or transmission of several major human diseases such as asthma, Legionnaire’s disease and osteoarthritis. Therefore, selective inhibitors of chitinases are now of considerable interest as new drug leads and biochemical probes. Until recently, few broad spectrum chitinase inhibitors had been identified. The natural cyclopentapeptide, argifin, has been shown to be a potent inhibitor of several bacterial-type family 18 chitinases including Aspergillus fumigatus chitinase B1 (AfChiB1). With the aid of high resolution X-ray structures we have designed and prepared linear fragments of the natural product cyclopentapeptide argifin using a combination of SPPS and solution phase synthesis. This has allowed us to determine that the Nmethyl guanylurea motif serves as a starting point for the generation of novel, drug-like, peptidomimetic inhibitors family 18 chitinases. We have also demonstrated that the cis configuration about the Arg(MC)-N-MePhe peptide bond is essential to retain any significant biological activity. This dipeptide motif is also found in another naturally occurring cyclopentapeptide, banyasin A, extracted from the cyanobacteruim Nostoc sp. Banyasin A also contains a rare +-amino acid, 3-amino-2-methyl-5E-octenoic acid (Amoa), in which the stereochemistry at the C3 and C5 of Amoa has not been resolved. The diastereoselective synthesis of Amoa for the preparation of banyasin A has also been established using chiral oxazolidinone-based aldol chemistry, which has allowed us to successfully prepare a single diastereoisomer of the natural product cyclopentapeptide incorporating this +-amino acid. New methodology for the preparation of argifin has also been developed to reduce the propensity towards the formation of undesired side products and to prepare the natural product on a larger scale.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:518107 |
| Date | January 2010 |
| Creators | Nathubhai, Amit |
| Contributors | Eggleston, Ian |
| Publisher | University of Bath |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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