The synthesis, structural characterization and biological evaluation of potential chemotherapeutic agents

Cathepsin proteases have been identified in many parasitic organisms and are involved in roles as diverse as tissue and skin penetration, virulence and immune invasion. Involvement in these key functions renders them potential targets at which to direct novel chemotherapeutic agents. The inhibitor N-benzoyl-L-Leu-Gly nitrile prepared in this laboratory was shown to possess significantly greater inhibitory potency on the liver fluke Fasciola hepatica cysteine cathepsin L like endoproteases over the known commercial inhibitor Z-Phe-Ala-CHN₂ at varying concentrations. The synthesis, structural characterisation and biological evaluation of a series of analogues of this active compound is now reported. Addition of fluorine atoms to the N-terminal benzoyl group and selective modification of the N-terminus is reported. These dipeptidyl derivatives were synthesized using the standard DCC/HOBt or EDC/HOBt protocols. These novel Cathepsin L inhibitors have been characterized by a wide range of spectroscopic techniques including ¹H, ¹³C, ¹⁹F NMR and ESIMS. The biological activity of these novel compounds was determined in a bioassay using Z-Phe-Arg-NHMec as a fluorogenic substrate. Resveratrol is a naturally occurring phyloalexin found in several plants but mainly in the skins of grapes. It has been shown to be produced in response to bacterial and fungal infections. It has been shown to exhibit various biological activities including anticancer, antifungal, antiviral, neuroprotective, anti-aging, and anti-inflammatory effects. The synthesis of fluorinated stilbenes containing the 3,5,4'-substituted backbone was accomplished. The compounds were synthesised via the Wittig reaction and the decarbonylative Heck reaction. In conjunction with fluorine, nitrogen was also used as a replacement for the oxygen atoms of the resveratrol structure. Full structural characterisation of these compounds was carried out followed by preliminary biological screening.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

Dublin City University

Year dc:date.issued

2008

Author dc:creator

• Moran, Brian W.

• Organic chemistry

Language dc:language

en