Specific aims of this project are to (1) synthesize fluoroketo unsaturated nucleosides of glucose and fluoroketo xylose with (a) 5-fluorouracil (b) cytosine (c) 6 azathymine; (2) to do a biological evaluation of these fluoro unsaturated nucleosides to find the extent of their anticancer/antiviral activity. Recent investigations in our laboratory have unequivocally shown that keto unsaturated nucleosides of 5'-fluorouracil with alpha-L-rhamnose inhibit significantly the in vitro growth of the following cell lines: murine leukemia (LI210), murine mammary carcinoma (FM3A), human beta-lymphoblast (Raji) and human T. lymphoblast (Molt/4F). Further, in vivo evaluation of one of the compounds has shown significant growth inhibitory activity against adenocarcinoma 755 tumors in BDF1 mice. Any influence of fluorine in the sugar moiety will be studied in this project, as the previous nucleosides did not have fluorine atom in the sugar part. The experimental design to achieve the synthetic goals involves: (1) preparation of 6-fluoro-6-deoxy glucose using diethyl amino sulfur trifluoride (DAST) on methyl 2,3,4 tri-O-acetyl-6-tosyl glucoside. (2) Convert the fluoro to glucal after removing the anomeric methyl group. (3) Coupling the glucal with the selected silylated base to get the 2,3 unsaturated nucleoside (4) oxidize the C4-OH group to get the desired fluoro keto unsaturated nucleoside. In the case of xylopento pyranose, an epoxide will be prepared from the unsaturated nucleoside. Fluorine will be introduced in the ring by epoxide opening. Long term objective of this project is to synthesize more of the unsaturated fluoro sugar nucleosides with different pyrimidine analogs to study the structure activity relation between fluoroketohexo and fluoro ketopento nucleosides since several fluoro nucleosides have shown anticancer and antiviral activity.
