Chemoenzymatic syntheses and anti-HIV-1 activity of glucose-nucleoside conjugates as prodrugs

Abstract

Phosphodiester linked conjugates of various nucleosides such as d4U, d4T, IdUrd, ddI, ddA, virazole, ara-A, and ara-C containing a glucosyl moiety have been described. These compounds were designed to act as prodrugs, where the corresponding 5'-monophosphates may be generated intracellularly. The synthesis of the glycoconjugates was achieved in good yields by condensation of a glucosyl phosphoramidite 7 with nucleosides in the presence of an activating agent. It was demonstrated that the glucose conjugates improve the water solubility of the nucleoside analogues, for example, up to 31-fold for the ara-A conjugate compared to that of ara-A alone. The new conjugates were tested for their anti-HIV-1 activity in human lymphocytes. These derivatives offer a convenient design for potential prodrug candidates with the possibility of improving the physicochemical properties and therapeutic activity of nucleoside analogues.

Figure 1

Comparative water solubility data of free nucleosides and prodrugs 10a-i.

Scheme 1

Synthesis of D-glucose phosphoramidite

Scheme 2

Synthesis of Nucleosyl D-Glucopyranosyl Phosphodiesters

Scheme 3

Enzymatic Synthesis of 3′- and 5′-O-Lev-IdUrd.

Scheme 4

Synthesis of formamidine base protected ddA

Scheme 5

Synthesis of virazole nucleoside precursor

Scheme 6

Synthesis of ara-adenosine precursor

Scheme 7

Synthesis of ara-cytidine precursor

Chart 1

Prodrugs of Phosphorylated Nucleosides