Synthesis of Novel Nitric Oxide Donors and Prodrugs of 5-fluorouracil
Author | : Tingwei Cai |
Publisher | : |
Total Pages | : |
Release | : 2005 |
ISBN-10 | : OCLC:62095498 |
ISBN-13 | : |
Rating | : 4/5 (98 Downloads) |
Book excerpt: Abstract: This dissertation describes my Ph. D. work that focused on the synthesis and evaluation of novel nitric oxide donors, and the synthesis of derivatives of 5-fluorouracil. In chapter 1, a series of alkyl and aryl N-hydroxyguanidines were synthesized and demonstrated to act as substrates of nitric oxide synthases (NOS). The discovery of these non-amino acid hydroxyguanidines as novel substrates also led to the discovery of a novel-binding mode of NOS. In chapter 2, in order to achieve site specific delivery of nitric oxide (NO), a new class of glycosidase activated NO donors has been developed. Glucose and galactose were covalently coupled to 3-morphorlinosydnonimine (SIN-1), a mesoionic heterocyclic NO donor, via a carbamate linkage at the anomeric position. The beta-glycosides were successfully prepared for these conjugates, while the alfa glycosidic compounds were very unstable. The new stable sugar-NO conjugates could release NO in the presence of glycosidases. Such NO prodrugs may be used as enzyme activated NO donors in biomedical research. In chapter 3, a new sialated diazeniumdiolate has been synthesized and the glycosylation product was exclusively an alfa anomer. This new nitric oxide donor exhibited significantly improved stability as compared to its parent diazeniumdiolate salts and it could be efficiently hydrolyzed by neuraminidase to release nitric oxide with a Km of 0.14 mM. The sialic acid-NO conjugate would be a valuable prodrug that targets NO to influenza viruses. In chapter 4, two classes of prodrugs of 5-fluorouracil (FU) were synthesized. The first type is FU-NO conjugate. The synthesized compounds showed greater cytotoxicities than 5-fluorouracil for DU 145 human prostate and HeLa cancer cells. The second type is carbohydrate-FU conjugate. A new reverse glycosadition was also developed to prepare sugar conjugates. In chapter 5, 7-carboxylindazole, as well as 5- and 6-carboxylindazoles was synthesized. These compounds were designed as isosteres of 7-nitroindazole, a well-known inhibitor of NOS. However, they did not show potent inhibition to NOS.