Total synthesis and structure-activity relationship studies of antifungal peptidyl nucleoside antibiotics

Part I. Total synthesis and structure-activity relationship studies of pyranosyl nikkomycin B and analogs. Through potent and selective inhibition of chitin synthase, the complex peptidyl nucleoside antibiotic nikkomycin B exhibits impressive antifungal activity against a variety of human pathogenic fungi. As the chitin biosynthetic pathway is absent in humans, chitin synthase inhibitors represent potential leads for the development of new generations of safe and more efficacious antifungal therapeutic agents.; In a hitherto unexplored structure-activity relationship study of the nikkomycins, the present research is directed at investigating the role of the carbohydrate ring size of the above natural products on their biological activity. Accordingly, the results of a study involving design, synthesis and biological evaluation of a carbohydrate ring-expanded pyranosyl analog of nikkomycin B are described in the first chapter of the thesis.; The synthesis was accomplished by separate construction of the amino acid side chain and the pyranosyl nucleoside segment of the target nikkomycin analog. Subsequent peptidic coupling of these components provided the desired product. A key element in the above synthetic strategy entailed utilization of D-serine towards rapid and efficient synthesis of a strategic aminopyranone intermediate, followed by de novo construction of the pyranosyl amino acid nucleoside segment on this versatile chiral platform.; The above synthetic route was also extended to obtain various side chain-modified 'second generation' analogs of pyranosyl nikkomycin B. Upon biological evaluation of the above compounds against a variety of clinically significant pathogenic fungi, several analogs demonstrated equipotent or increased antifungal activity compared to the parent natural product.; Part II. Studies toward the total synthesis of amipurimycin. The complex peptidyl nucleoside Amipurimycin is an antifungal natural product with a uniquely substituted pyranosyl sugar core. Insufficient biological information on the mode of its action, and the lack of any total synthetic route to amipurimycin prompted us to initiate a total synthesis of this bioactive natural product.; Thus, starting from the chiral aminopyranone intermediate as developed during my earlier studies, a stereoselective synthesis of the fully functionalized, C3-branched pyranosyl amino acid core of amipurimycin could be achieved. Unfortunately, numerous attempts to incorporate the desired 2-aminopurine nucleobase towards formation of the corresponding nucleoside remained unsuccessful. It was however possible to introduce a simpler pyrimidine nucleobase (thymine) onto the amipurimycin sugar core, resulting in a thymine analog of amipurimycin. Subsequent coupling of the above nucleoside component with the cispentacin side chain, as present in amipurimycin, culminated in the total synthesis of an unnatural 'thymine amipurimycin' analog.