Date of Award

5-4-1990

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Abstract

The overall objective of this research was to find methods for incorporating CF$\sb2$ groups into nucleosides in order to obtain biologically active molecules. The nucleoside analogs were designed to be inhibitors of DNA synthesis and to block viral replication. Particular emphasis was directed toward analogs with the potential to inhibit HTLV-III encoded reverse transcriptase. The specific objectives were, (a) to find ways to replace each of the deoxyribose oxygens by the isosteric-isopolar CF$\sb2$ group, and (b) to replace the 2$\sp\prime$-CH$\sb2$ and 3$\sp\prime$-CHOH groups by a CF$\sb2$ group. Emphasis was placed on a detailed investigation of the introduction of the CF$\sb2$ group into carbohydrate analogs via reactions of aldehyde and ketone derivatives. New analogs were to be provided to other laboratories for testing as antiviral agents and as inhibitors of enzymes involved in DNA biosynthesis (via DNA polymerase or reverse transcriptase).Strategies were outlined for the synthesis of four fluorine-substituted compounds: 2-deoxy-2,2-difluoro-$\alpha$-D-ribofuranose, 3$\sp\prime$-deoxy-3$\sp\prime$,3$\sp\prime$-difluorothymidine, 1-(5-O-trityl-2,3-dideoxy-3-difluoromethyl-$\beta$-D-threo-pentofuranosyl)thymine, and 4,4-difluoro-3-(S)-hydroxymethyl-5-(S)-aminocyclopentene. Of the four compounds, 3$\sp\prime$-deoxy-3$\sp\prime$,3$\sp\prime$-difluorothymidine was successfully prepared; the synthetic route to 2-deoxy-2,2-difluoro-$\alpha$-D-ribofuranose was successful up to the formation of 1,3,5-tribenzoyl-$\alpha$-D-ribofuranose-2-dithioketal; the synthetic route to 1-(5-O-trityl-2,3-dideoxy-3-difluoromethyl-$\beta$-D-threo-pentofuranosyl)thymine was successful up to the formation of 5$\sp\prime$-O-trityl-2$\sp\prime$,3$\sp\prime$-dideoxy-3$\sp\prime$-cyanothymidine; and the synthesis of 4,4-difluoro-3-(S)-hydroxymethyl-5-(S)-aminocyclopentene was successful up to the formation of 2-azabicyclo (2.2.1) hept-4-ene-7-onediethylketal.3$\sp\prime$-Deoxy-3$\sp\prime$,3$\sp\prime$-difluorothymidine was sent to Dr. Eric De Clercq in Belgium for antiviral screening with emphasis on its anti-HIV (AIDS) activity. The screening showed that the compound was not very active against HIV, which was surprising because the 3$\sp\prime$-monofluoro analog was known to be extremely active. Postulates as to why this should be so are discussed.

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