Base-functionalized carbocyclic nucleosides: design, synthesis, and mechanism of antiviral activity

Abstract

New carbocyclic ribonucleosides with unsaturated groups at the C-2 position of the nucleobase were designed as potential RNA antiviral compounds. The design was based on the expectation that the monophosphates of these compounds would be inhibitors of the enzyme, IMPDH. Appropriate methodologies were developed to achieve the target molecules. Results from the initial in vitro antiviral studies are mentioned. The IMPDH-associated mechanism of the antiviral activity of the most active compound is supported by enzyme inhibition studies.

Figure 1

3-Deazaguanosine and 2-vinylinosine are IMPDH inhibitors as their monophosphates

Figure 2

Structures of target compounds

Figure 3

Progress curves for the inhibition of IMPDH by inhibitor 8-MP monitored by the UV absorption of cofactor product, NADH, at 340 nM (see reference 15 for detailed procedure for inhibition studies).

Figure 4

Plot of K_obs versus inhibitor concentration derived from progress curves of Figure 3. The relevant equations are: A - A_o = V_o/K_obs[1-exp(-K_obst) and K_obs = k_on[I]/(1 +[IMP]/K_m.

Scheme 1

Synthesis of a carbocyclic analog of 2-vinylinosine

Scheme 2

Methodology to purine carbocyclic nucleosides with Michael acceptors at C-2.

Scheme 3

Carbocyclic hypoxanthine nucleosides with other Michael acceptors.