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Toward the development of y-lactones and y-lactams as protease inhibitors
Date
2012
Abstract
A select set of y-lactones, y-lactams and related bicyclic y-lactams - pyrrolothiazole[2,1b]thiazoles - were designed, synthesised and evaluated enzymatically as inhibitors of the serine proteases, elastase, and (to a very limited extent) thrombin. Computational docking was used to predict the suitability of substituent groups on the y-lactone and y-lactam scaffolds for occupancy of the primary binding pockets that border the enzyme active site. Weak activity against thrombin was observed for one of the pyrrolothiazoles (108 showed a 40% reduction in enzyme activity when incubated for 40 min at 1 mM), however, the levels of inhibition of elastase were considerably lower for all the structures examined. It was considered that the inherent reactivity of the y-lactone and y-lactam scaffolds studied here was too low for effective acylation of the active-site serine of elastase. The synthetic methodology that was used was based on mucohalic acid chemistry that allowed for a modular synthesis of the various scaffolds. For both the mono and bicyclic structures, the C-3 vinylic halogen of mucohalic acid was initially replaced using a 1,4-addition-elimination process to give a muco-derivative which, when reacted with D-penicillamine lead to the pyrrolothiazole core structure, and when treated with diphenyldiazomethane was converted to a ring-opened ester that proved to be a key unit for formation of y-lactams bearing an electron-withdrawing group tosyl group on the lactam nitrogen atom. The formation of a sulfonylimine from the ringopened ester proceeded smoothly when treated with a tellurodiimide reagent, prepared by reaction of tellurium powder and chloramine-T. Reaction of the sulfonylimine with a hydride reagent generated the monocyclic y-lactam. Reaction of the ring-opened ester with a hydride reagent proved to be an effective method for formation of the monocyclic y-lactones, while reaction of this ester with a methyl Grignard reagent led to a monocyclic y-lactam with a methyl group in the 5-poistion. In the case of each of these monocyclic units, and the pyrrolothiazole core structure, the remaining vinyl halide was then replaced so as to complete the installation of the desired substituents. This last displacement was effected both by azide ion and via Suzuki-Miyaura coupling using aromatic boronic acid or ester reagents. A Click reaction with the azide derivatives allowed for installation of a phenyltriazole group.
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peer-reviewed
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Mullane_2012_towards.pdf
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