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

The design and synthesis of potent chemotherapeutics offers one of the most successful routes for the treatment of disease. A series of amino acid, dipeptidyl and stilbenyl derivatives have been synthesised and evaluated as potential therapeutic agents. These compounds were fully characterised by a range o f spectroscopic techniques including; IR, IH, 13C, 19F, 3 IP, DEPT 135 and HMQC NMR in addition to ESIMS. X-ray crystal structures were also obtained in certain cases. Multidrug resistance (MDR) is used to define resistance whereby cells become resistant to different drugs with no obvious structural resemblance and with different cellular targets. The preparation o f TV-fluorobenzoyl amino acid derivatives has resulted in the synthesis o f multidrug resistance modulators. TV-pentafluorobenzoyl-L-alanine methyl ester 81 was the most potent derivative. This compound although relatively non-toxic was shown to increase the potency o f the anticancer drug epirubicin by 65%. Fasciolosis is not only an important human disease but also affects cattle and sheep worldwide causing economic losses of approx 2 billion dollars. Potent inhibitors of Fasciola hepatica cathepsin L endoproteases have been developed. These dipeptidyl derivatives were synthesised by using the standard 1,3-dicyclohexylcarbodiimide (DCC) or l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt) protocol. N-4- fluorobenzoyl-L-leucine-glycine nitrile 151 was shown to be the most active compound with an IC50 value o f 2.78 |j.M recorded. a-Chymotrypsin has served as a prototypical enzyme for the serine proteases and has been very useful as a model target enzyme for the development of compounds of pharmacological interest. A series of dipeptidyl phosphonate esters were prepared by standard EDC/HOBt protocol. jV-4 -fluorobenzenesulphonyl-glycine-phenylalaninep-(OPh) 2 165 was the most potent derivative with an IC50 value o f 16.15 jiM against a-chymotrypsin. Resveratrol found in grapes is a naturally occurring phytoalexin formed in response to fungal infections. It has been shown to exhibit various biological properties including antifungal, anticancer, estrogenic and heart protecting activities. The synthesis of fluorinated analogues of this bioactive compound were carried out using a decarbonylative Heck reaction with preliminary biological results indicating that (£)-l-(4-acetoxystyryl)-3,5- difluorobenzene 192 was a potent growth inhibitor o f breast, lung and central nervous system cancer lines. At a concentration of 100 (.iM the growth of central nervous system cancer waslimited by 99%