Boronic Acid Analogs of Nucleoside-5'-Phosphates

A major problem with the use of nucleoside phosphates as antiviral and antitumor drugs has been their inability to penetrate cell membranes. Additionally, nucleoside phosphates are susceptible to phosphatases and nucleases, which reduce their in vivo life time. Replacement of the charged phosphate group with uncharged boron containing moieties should not only enhance their cell permeability, but the new analogs are expected to be resistant to phosphatases and nucleases. The long term objective is to synthesize boronated nucleoside phosphates as analogs of normal or sugar modified nucleosides. These compounds may be prepared by two methods: 1) by direct modification of a nucleoside, or 2) by attachment of a modified sugar moiety to the base. The Phase I effort will mainly concentrate on the synthesis of an analog of acyclovir monophosphate and to develop methods that may be utilized for the synthesis of analogs of other nucleoside phosphates in Phase II. The newly synthesized compound will be tested for its effect on certain enzymes and its potential antitumor and antiviral activity. The boronated nucleotides may be useful in a number of ways including 1) as tools for studying mechanism of action of enzymes, 2) as antiviral and antitumor agents, and 3) as carriers of boron-10 for boron neutron capture therapy.