Göttingen, Univ., Diss., 2003. / Computerdatei im Fernzugriff.

Göttingen, Universiẗat, Diss., 2003.

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.

Thesis (Ph. D.)--Pennsylvania State University, 1994. / Includes bibliographical references.

Chitin, a linear polymer of N-acetylglucosamine, is an essential structural component of fungal, nematode and insect pathogens but is not found in human physiology. Chitinases, which hydrolyze this polymer, play a key role in life cycle of these pathogens and associated pathogenesis. Consequently chitinase inhibitors have generated a lot of interest given their potential as insectides, fungicides and antimalarials. Herein, approaches are reported to the synthesis of some non-sugar based chitinase inhibitors: the cyclic pentapeptide natural products argifin, banyasin A and diketopiperazines related to the natural product CI-4. In order to improve the efficiency of production of argifin and facilitate SAR on analogues of the natural product, a revised synthesis of argifin has been developed. The synthesis of argifin was carried out by a combination of solid-phase and solution chemistry. The assembly of the linear peptide was carried out by SPPS and the cyclisation was performed in solution. The protecting groups chosen for the Asp and Arg residues were removable by hydrogenolysis, as this allowed aspartimide formation under acidic conditions to be avoided. Only one HPLC purification was required at the final step; argifin was isolated in 19% yield, compared to 18% yield for the first synthesis by Dixon et al. Banyasin A contains the same essential Arg(MC)-MePhe dipeptide motif as argifin and so it is of considerable interest as a potential Family 18 chitinase inhibitor. The synthesis of Amoa (3-amino-2-methyl-5E-octenoic acid) a rare amino-acid present in banyasin A was investigated. An advanced intermediate for the synthesis of Amoa was successfully obtained via chiral pool chemistry in an 8 step sequence from L-Asp. This involved preparation of a selectively protected β-methyl-substituted Asp derivative, which was then homologated to the β-amino-acid via Arndt-Eistert chemistry to give (3R,4R)-3-(((benzyloxy)carbonyl)amino)-4-methyl-5-oxo-5-allyloxypentanoic acid in 27% yield for the final step. The cyclic dipeptide CI-4, cyclo (L-Arg-D-Pro) is a weak inhibitor (IC50 = 1.2 mM) of Family 18 chitinases, however its binding efficiency index (BEI) is comparable to more potent inhibitors such as argifin. Some analogues of CI-4 show promising activity against a typical bacterial type Family 18 chitinase, SmChiB1 from Serratia marcescens. The cyclic dipeptide should therefore be a useful starting point for the development of more effective and selective inhibitors of this enzyme class. A series of cyclo (Xaa-Pro)-based dipeptides were synthesized, with different Xaa such as L/D-Pro, Gly, L-Ser, L/D-Arg, D-His, D-Phe, with yields ranging from 12 to 84%. Preliminary biological data confirm that cyclo(D-Xaa-D-Pro) may be a novel template for the development of new drug-like inhibitors of Family 18 chitinases.

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

No description available.

Thesis (Ph.D.)--Murdoch University, 2006. / Thesis submitted to the Division of Science and Engineering. Includes bibliographical references (leaves 164-182).

Thèses (M.Sc.)--Université de Sherbrooke (Canada), 2001. / Titre de l'écran-titre (visionné le 20 juin 2006). Publié aussi en version papier.